Synthesis of beaded poly(vinyl ether) solid supports with unique solvent compatibility

Article abstract of DOI:10.1016/j.polymer.2010.04.026

Poly(vinyl ether) gels SLURPS (Superior Liquid Uptake Resin for Polymer-supported synthesis) with low cross-linking levels have been synthesized for the first time in beaded form using a non-aqueous inverse suspension polymerisation approach. The synthetic protocol was optimized with regards to several parameters including reactions conditions, type and concentration of suspension stabilizer and controlled low temperature addition of co-initiator. Particle size measurements confirm the production of beads with average diameters of 700-950 μm. Optimization of the monomer composition of the poly(vinyl ether) gels resulted in a novel beaded polymer support with considerably improved as well as unique swelling characteristics in solvents ranging from hexane to water. The synthetic utility of the new gel was confirmed by carrying out a set of transformations with complete conversion leading to a useful amino and hydroxy terminated solid-phase precursor resin. Reaction progress could be monitored easily by ¹H and ¹³C gel-phase NMR.

Full text of DOI:10.1016/j.polymer.2010.04.026

Polymer 51 (2010) 2984e2992
Contents lists available at ScienceDirect
Polymer
journal homepage: www.elsevier.com/locate/polymer
Synthesis of beaded poly(vinyl ether) solid supports with unique
solvent compatibility
,
,
,
*
Barnaby W. Greenland a 1, Shuyuan Liu a, Gabriel Cavalli a 2, Esat Alpay b, Joachim H.G. Steinke a
a Department of Chemistry, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
b Department of Chemical Engineering and Chemical Technology, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Poly(vinyl ether) gels SLURPS (Superior Liquid Uptake Resin for Polymer-supported synthesis) with low
cross-linking levels have been synthesized for the first time in beaded form using a non-aqueous inverse
suspension polymerisation approach. The synthetic protocol was optimized with regards to several
parameters including reactions conditions, type and concentration of suspension stabilizer and
controlled low temperature addition of co-initiator. Particle size measurements confirm the production
Received 23 September 2009
Received in revised form
28 March 2010
Accepted 13 April 2010
Available online 28 April 2010
of beads with average diameters of 700e950 mm. Optimization of the monomer composition of the poly
(vinyl ether) gels resulted in a novel beaded polymer support with considerably improved as well as
unique swelling characteristics in solvents ranging from hexane to water. The synthetic utility of the new
gel was confirmed by carrying out a set of transformations with complete conversion leading to a useful
amino and hydroxy terminated solid-phase precursor resin. Reaction progress could be monitored easily
by 1H and 13C gel-phase NMR.
Keywords:
Poly(vinyl ether)s
Suspension polymerisation
Solid-phase synthesis
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
iterative chemical reaction schemes like those used in peptide and
oligonucleotide syntheses have been developed into commercially
Over many years polymer supports have become a common tool
in synthesis and are of particular importance in solid-phase
synthesis of peptides, oligonucleotide and for drug discovery [1e9].
Since the pioneering experiments by Merrifield [10] the use of
polymer supports in the laboratory has become ubiquitous, driven
in many cases by the ease of use, separation and automation
expanding its utility into high-throughput experimentation and
combinatorial drug and materials synthesis [11e15]. Although
soluble polymers have received some attention [6,16,17] insoluble,
inert and cross-linked supports form the majority of solid-phases
exploited for chemical transformations [4]. Typically, a starting
material of interest is attached at a specific location to the support
via a linker molecule, the latter designed to withstand all reaction
conditions used in a multi-step synthetic sequence, before release
of the final product from the polymer support under a set of specific
cleavage conditions [4,9,18,19]. This process is amenable to simplify
and automate purification and isolation steps. Polymer supports for
important processes. On the other hand multi-step transformations
have proven to be more difficult to translate into solid-phase
processes. Perhaps the most crucial reason is the unavailability of
a polymer support that is chemically inert to reagents and catalysts
while being compatible with the widest possible range of solvent
polarities. In the limit a support is desirable that, other than
imparting insolubility to the substrate, performs as if the same
reaction had taken place in solution.
To approach a solvent-like reaction environment a considerable
range of polymer supports have been designed and evaluated since
Merrifield opted for chloromethylated polystyrene (PS) gel beads in
his seminal work of synthesising a tetrapeptide [1,10]. The PS gel
format itself has been modified and made more solvent compatible
through grafting of mainly hydrophilic polymers (poly(ethylene
glycol) (PEG) in particular). Greater structural variations to improve
on the original support have included individually or in combina-
tion chemically different polymer backbones, various polymer
architectures and developments of new physical formats [4,18,19].
Our work in this area has been aimed at developing a “universal”
support, which we have defined as one inert to most common
reaction conditions and reagents in addition to being compatible
with as broad a spectrum of solvents as possible. Towards this goal
we identified gel-type cross-linked poly(vinyl ether)s (PVE) as
suitable candidates for this task which we termed SLURPS (Superior
* Corresponding author. Tel.: þ44 2075945852; fax: þ44 2075945804.
E-mail address: j.steinke@imperial.ac.uk (J.H.G. Steinke).
1
Present address: Department of Chemistry, University of Reading, White-
knights, Reading, RG6 6AD, UK.
2
Present address: Division of Chemical Sciences, Faculty of Health & Medical
Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK.
0032-3861/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.polymer.2010.04.026

B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
2985
OMe
OMe
O
O
O
O
O
O
O
OAc
MeO
i
+
+
O
OMe O
O
OMe OMe OAc
O
O
O
Ac
O
SLURPS-OAc
1
2
3
SLURPS-OAc
Scheme 1. Synthesis of SLURPS-C4-OAc. i) CH2Cl2, BF3OEt2, ꢁ78 ꢀC to ꢁ10 ꢀC, H2O/NH3, 100% conversion, 80% yield.
As we have so far produced our SLURPS-gels as random particles
we were keen on producing a support format which would be more
convenient for resin handling and thus more widely usable. Despite
some reservation that we may not be able to identify a biphasic
solvent system to carry out suspension polymerisation, as our poly-
mer support swells in most solvents, we set out to produce SLURPS
directly as beaded polymer supports to enhance their versatility.
2. Results and discussion
2.1. Beaded SLURPS synthesis
Beaded polymer supports are typically produced by radical
polymerisation of a suspension with water as the continuous phase.
Vinyl ethers used in this study can only be homopolymerized via
cationic polymerisation methods proceeding at temperatures well
below 0 ꢀC, ruling out water as continuous phase. Accounting for
these restrictions, precedent for a cationic suspension polymeri-
sation of vinyl ethers has been provided by deLeuze and co-workers
a few years ago [22]. Their system uses a partially fluorinated
copolymer as inverse suspension stabilizer and perfluorooctane as
non-aqueous continuous phase. Chemical initiation at low
temperatures still proved too reactive, but they found that photo-
polymerisation at room temperature was successful, albeit
requiring 50 mol% cross-linking levels to impart enough rigidity on
the polymer beads to minimize agglomeration during the reaction.
SPOCC (Superpermeable Organic Combinatorial Chemistry)
supports developed by Meldal et al. have also been described in
beaded form as the result of a cationic ring-opening polymerisation
of oxetane-capped monomers employing silicone oil as water
substitute and a custom-designed stabilizer copolymer containing
trimethylsiloxy-dimethylsilylpropyl sidechains [23]. It is apparent
from these two examples, which are the only ones applicable to our
target, that identifying appropriate conditions for a cationic inverse
suspension polymerisation is non-trivial. Successful bead produc-
tion requires an effective suspension stabilizer, especially in this
case as the low Tg of the resulting polymer beads increases further
the tendency of the forming beads to agglomerate. Good control
over the strongly exothermic nature of vinyl ether polymerisation is
Fig. 1. Optical image of a representative sample of beaded SLURPS-gels.
Liquid Uptake Resin for Polymer-supported synthesis) [20,21]. In
our initial report we demonstrated that these poly(vinyl ether)
networks can be synthesized with precise control over loading
levels, are amenable to efficient functionalization whilst main-
taining good swelling performance across a wide spectrum of
solvent polarities. More recently we showed that SLURPS-gels
perform well as solid-phase in peptide synthesis producing
pentapeptide Leu-enkephalin [21]. Purity levels were equivalent to
those achieved using the best available commercial resins for this
synthesis at comparable loading levels without any need for resin
optimization. In addition we showed SLURPS to produce the
pentapeptide even at more than a five-fold increased loading level
(8.5 mmol/g, a loading level unprecedented in peptide synthesis)
albeit with some loss of product purity. Furthermore through
organic transformation needing aqueous reaction conditions we
illustrated the excellent compatibility of SLURPS for highly polar
water-based reaction milieus.
Fig. 2. Analysis of the particle size distribution of SLURPS-beads in MeOH as a function of surfactant levels.

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B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
O
O
OMe
OMe
O
i
+
+
OAc
MeO
n
O
OAc
O
1
2
3a, n = 0
3b, n = 1
3c, n = 2
SLURPS-C2-OAc (containing 3a)
SLURPS-C4-OAc (containing 3b)
SLURPS-C6-OAc (containing 3c)
Scheme 2. Synthesis of SLURPS-gels with varying spacer groups in the cross-linker. i) BF3OEt2, ꢁ78 ꢀC, 100% conversion (all gels), isolated yields: 80% SLURPS-C2-OAc, 76% SLURPS-
C4-OAc; 75% (SLURPS-C6-OAc).
also needed and proved problematic for Deleuze et al. [22]. In our
particular case additional challenges were to produce beads with
only a few mol% of cross-linker (given by the composition of the
random particle SLURPS-gels) and to find a continuous phase
solvent that was immiscible with a monomer composition which
results in a polymer network with a very broad range of solvent
compatibility. As we will show in the following, careful optimiza-
tion of reaction conditions and the right choice of solvent and
suspension stabilizer allowed us to obtain the desired beaded
support.
During our initial work on bulk SLURPS-gel,[20] synthesized as
random gel particles at low temperature, we had conducted
a thorough optimization of the reaction conditions, focusing
sequentially on reaction temperature, co-initiator, quenching agent
and solvent (Scheme 1).
This optimization process resulted in identifying conditions that
gave 100% conversion of the vinyl ether monomers and 80% iso-
lated yield of the SLURPS-gel, with the remainder being micro-
particles which passed though the sintered glass filter. It was clearly
judicious to seek conditions to produce SLURPS-beads that
mimicked these reaction conditions as closely as possible. As dis-
cussed previously, it was imperative that we had to identify
a solvent replacement for the aqueous phase as water would be
incompatible with the cationic polymerisation chemistry which we
optimized for the bulk synthesis of SLURPS. Eventually, therefore,
we selected perfluorohexane (PFH) as a relatively inexpensive,
readily available, aprotic and fluorophilic continuous phase. We
paired the perfluorinated solvent with bromochloro methane
(BCM), which we found to produce a more stable suspension than
CH2Cl2, as a result of the increased incompatibility with the
continuous phase at the polymerisation temperature (zꢁ50 ꢀC).
With the selection of a fluorous continuous phase we tested a small
number of dispersants with a nonionic fluorinated polymeric
surfactant (FC-4430 from 3M) producing the best results.
Addition of a solution of monomers 1, 2 and 3 in BCM to PFH
containing the polymeric surfactant produced a biphasic system
containing about 10% by volume of monomers. Stirring this mixture
at room temperature using a three blade metal propeller driven by
an overhead stirrer at speeds of up to 800 rpm was ineffective in
producing a stable emulsion. Only upon cooling of the system to
ꢁ78 ꢀC phase separation into dispersed droplets occurred, as
indicated by the appearance of milk-like, opaque heterogeneous
mixture. All attempts to initiate the reaction adding BF3.EtO2 at
ꢁ78 ꢀC followed by allowing the reaction mixture to warm to room
temperature resulted in the rapid formation of a viscous sludge
rather than discrete beads. The gel-phase 1H NMR spectrum of this
material was identical to that of SLURPS-gels synthesized via bulk
polymerisation though. This suggested that whilst the new
“suspension” reaction condition did not inhibit the polymerisation,
under these specific conditions the biphasic system was not stable
enough to produce the desired beaded materials.
We speculated that addition of the co-initiator (kept at ambient
temperature) into the chilled suspension may be increasing the
temperature of droplets enough to break down the suspension,
whilst simultaneously initiating the polymerisation, or vice versa,
producing the observed unbeaded product. Our rationale was
consistent with the observations that a suspension only forms at
temperatures below ꢁ30 ꢀC, and that during our studies into the
bulk polymerisation of SLURPS we found that whilst the polymer-
isation kinetics are very slow at ꢁ78 ꢀC the reaction proceeds
quickly at slightly raised temperatures (ꢁ65 ꢀC to ꢁ55 ꢀC) [20].
Thus, we concluded that it may be possible to retain suspension
stability if a way could be found to introduce the co-initiator so that
the temperature remain close to ꢁ78 ꢀC during addition and to
agitate the biphasic system long enough to ensure homogeneous
distribution of the co-initiator throughout the suspension droplets.
Therefore as a second iteration of beaded SLURPS-gel synthesis, the
co-initiator was precooled via dropwise addition onto the metal
propeller shaft with drops forming a trail of liquid slowly traveling
down the cold (zꢁ78 ꢀC) metal shaft of the propeller into the
vigorously stirred emulsion held at ꢁ78 ꢀC (internal reaction
temperature). After addition of the co-initiator was complete the
reaction was left for 30 min at this temperature to allow the co-
initiator to disperse homogeneously throughout the droplet phase
without any apparent polymerisation taking place. Slowly
increasing the internal reaction temperature to ꢁ40 ꢀC over
approximately 25 min resulted in individual spheres of gel
25
20
15
10
5
0
i
OH
O
+ MeI
O
O
Solvent
4
5
Fig. 3. Equilibrium swelling performance of SLURPS-gels with varying cross-linker
(XL) spacer lengths.
Scheme 3. Synthesis of methoxyethyl vinyl ether. i) KOH, 0 ꢀC to r.t., 18 h, 72%.

B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
2987
O
O
O
O
O
Cl
O
O
O
O
O
i
+
+
OMe O
O
OMe OMe
O
O
Cl
5
6
3a
BLURPS-Cl
Scheme 4. Synthesis of BLURPS-Cl with monomer ratio 5:6:3a ¼ 85:11:4 mol%. i) BF3OEt2, ꢁ78 ꢀC, 100% conversion, 78% yield.
an average diameter of between 870 and 930
bead size of about 60
m
m. A decrease of the
m
m requires an increase in surfactant
concentration from 0.4% to 1.2% and does not affect significantly the
polydispersity of bead sizes (Fig. 2). The influence of the surfactant
concentration is modest though and does not allow us to control
the size of the beads within a broader range.
The obtained beads exhibited low surface roughness and,
together with the absence of bead clusters or insoluble lumps of
beads, both achieved whilst maintaining complete monomer
conversion, lead us to conclude that conditions have been identi-
fied which are close to those needed for a typical suspension
polymerisation.
For a support to become truly “universal” one key aspect we
needed to enhance is the already promising solvent compatibility
of our original SLURPS further [20,21]. Criteria for improvements
are extension of the solvent range as well as a more even swelling
response of the gel across a wide range of solvent polarities. Thus
we decided to revisit the original SLURPS synthesis (Scheme 1) and
investigate the effect that altering the monomers and their relative
feed ratios has on the swelling characteristics of the resulting gels.
It was apparent that the original one pot polymerisation of SLURPS-
gels could be readily adapted to include a range of monovinyl (1, 2)
and divinyl monomers (3) thus enabling a family of related SLURPS-
gels to be generated without the need of re-optimizing the poly-
merisation conditions each time.
For the first iteration of this work it was decided to change the
length of the spacer between the vinyl ether groups on the cross-
linker, as this would represent the smallest structural change
from the original SLURPS-gel. Thus two new SLURPS-gels were
synthesized with either an ethyl (Scheme 2, 3a, n ¼ 0) or a hexyl
(Scheme 2, 3c, n ¼ 2) spacer group in the cross-linking monomer
(XL).
Fig. 4. Analysis of the particle size distribution for BLURPS-Cl.
appearing in the reaction flask. After 2 h at this temperature the
surface of the reaction vessel was coated with beads and the liquid
phase(s) had become transparent, suggesting complete consump-
tion of the starting materials. This was confirmed by analyzing an
aliquot of the liquid phase by 1H NMR spectroscopy which revealed
the absence of any residual vinylic protons associated with the
starting monomers. Finally, the reaction was allowed to warm to
room temperature and subsequently quenched with an ammonia/
water mixture whereupon the colourless beads were easily
collected by filtration.
Analysis of the resulting beads by optical microscopy showed
that isolated beads were in most cases only approaching a uniform
spherical shape, some though turned out to possess ideal spherical
topology (Fig. 1).
In order to evaluate reproducibility and to what extent we could
exert control over the size of the beads, the synthesis was repeated
with three different levels of surfactant concentration (0.4, 0.8 and
1.2 wt%). With increasing surfactant concentration the bead size
decreased as was determined by particle sizing using static laser
light scattering (Fig. 2). All distributions were bimodal, with the
local maximum at around 120 mm representing less than 3% of the
total particle volume. The vast majority of polymer beads possessed
Fig. 6. Comparison of the equilibrium swelling of BLURPS-Cl beads with differing XL
Fig. 5. Equilibrium swelling properties of SLURPS-C4-OAc and BLURPS-Cl.
ratios as determined by volumetric and gravimetric analysis.

2988
B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
O
OMe
OMe
OMe
OMe
OMe
Cl
NH2
N
i
ii
MeO
MeO
MeO
O
OMe
BLURPS-N-Phthalimide
BLURPS-Cl
BLURPS-NH2
Scheme 5. Synthesis of BLURPS-NH2. i) Potassium phthalimide, NaI, DMF, 100 ꢀC, 18 h, 82%; ii) EtOH, H2NNH2, reflux, 18 h, 94%.
Comparison of the swelling profiles of the three SLURPS-gels
(Fig. 3) revealed that introduction of a hexyl spacer (SLURPS-C6-
OAc) decreased the swelling performance markedly in almost all
the solvents tested, whilst shortening the cross-linker to an ethyl
group (SLURPS-C2-OAc) had little effect on the swelling perfor-
mance over the original gel composition (SLURPS-C4-OAc). One
could rationalize the swelling response for the shorter cross-linker
as a balance between its increased polarity, yet the shorter spacer
length generates a gel network with a reduced maximum volume of
swelling, in effect the benefits of the polarity increase are coun-
teracted by a less extendable network. The exception being the
response to water which we cannot explain at the moment. The
more lipophilic nature of the hexyl-spaced cross-linker is reflected
in the reduced swelling in polar solvents and the significant
increase for swelling in hexane, but surprisingly not for toluene.
Possibly solvent interactions with the cross-linker are only
significant in hexane, and the lack of swelling in water and meth-
anol could be attributed to a gel in which all cross-linking points
have collapsed and severely restrict the level to which the linear
polymer chain segment of the network can interact and respond to
polar solvents. Although the use of the hexyl spacer has reduced the
maximum swelling levels in all solvents but hexane; the absolute
differences in the levels of swelling between individual solvents has
become less (i.e. more balanced) which is desirable.
2.2. Varying the monovinyl methoxy monomer (2)
The set of cross-linkers studied brought to the fore that in order
to improve the swelling performance of the gels towards individual
solvents it would be necessary to alter the monovinyl constituents
(1, 2) of the polymer, which make up the majority of the structure. It
was hoped that by positioning the methoxy groups on 1 closer to
Fig. 7. 1H and 13C NMR spectra of BLURPS-Cl gel, BLURPS-N-phthalimide and BLURPS-NH2 (top to bottom respectively).

B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
2989
O
O
O
O
O
O
O
O
O
i
+
+
OMe O
O
OAc OMe OMe
O
O
O
OAc
5
7
3a
BLURPS-OAc
Scheme 6. Synthesis of BLURPS-OAc with monomer ratio 5:7:3a ¼ 85:11:4 mol%. i) BF3OEt2, ꢁ78 ꢀC, 77% yield.
the polymer backbone the resulting material would behave more
akin to linear polyethylene glycol (PEG) and extend the range of
solvent interactions to those solvents at the extremes of the
polarity scale. Accordingly, the known methoxyethyl vinyl ether (5)
[24] was synthesized in 72% yield (Scheme 3) as the shorter-chain
analogue for the original methoxybutyl vinyl ether monomer (1).
Additionally, it was possible to make use of the commercially
available 2-chloro vinyl ether (6, Scheme 4) as the short chain
analogue rather than functional monomer 2, which has to be
synthesized.
Submitting monomers 5, 6 and 3a, to the same reaction condi-
tions as described earlier for the synthesis of the beaded SLURPS-
gel resulted in the formation of essentially colourless beads of what
we elected to call BLURPS-Cl (in good analogy to SLURPS and
highlighting the significantly improved performance, we propose
the acronym BLURPS being “Beguiling Liquid Uptake Resins for
Polymer-supported Synthesis”) (Scheme 4).
The ability to prepare these novel gel beads from easily acces-
sible starting materials in a robust suspension polymerisation
process has clear advantages in producing larger quantities of this
material for further evaluation and potential commercial exploi-
tation. Analysis of the particle size distribution for BLURPS-Cl
(Fig. 4) showed essentially the same bimodal size distribution as
observed during the SLURPS bead synthesis with the majority of
the beads in the sample (w93%) falling within the 0.1e2 mm size
range.
to now we have not been able to obtain the intended beaded gels
containing 3% mol XL. Instead we were only able to produce viscous
oils, suggesting that the minimum level of cross-linker needed to
confer mechanical properties to the gel during the polymerisation
had previously been reached. Conversely, beads containing 5 mol%
cross-linker could readily be synthesized but showed, as expected,
reduced levels swelling across the entire solvent polarity range
(Fig. 6).
In the course of our investigations we also experimented with
faster methods to screen gels more quickly for their changes in
solvent responses. In Fig. 6 we show the swelling ratios of the 4 and
5 mol% cross-linked gels obtained by our well-established gravi-
metric method [20] are compared to a much simpler volumetric
alternative. During this new procedure the gels were packed
loosely inside a plastic syringe and a constant stream of solvent
(and solvent gradients when switching from one solvent to the next
in a continuous mode) was passed through the syringe barrel,
accompanied by gentle agitation to increase the packing efficiency.
In this manner it is possible to screen a polymer gel like ours within
a few hours for its solvent response across the entire polarity scale
of interest as the overall swelling response pattern is very similar to
that obtained via the gravimetric method. The increased absolute
values of swelling can be explained by inefficient packing and can
only be used as a rough guide for comparing the trends in the
solvent responses of gels with each other.
This pleasing result showed the polymerisation conditions to be
tolerant of chlorinated, as well as acetylated monomers (Scheme 6)
which effectively shortens the synthetic route to halogenated gels
(versatile intermediates) for the introduction of common linkers
used in SPOS (Solid-Phase Organic Synthesis) and SPPS (Solid-
Phase Peptide Synthesis) by three steps when compared to the
initial SLURPS-Br synthesis.
The swelling behaviour of the new gel (BLURPS-Cl) was deter-
mined in an identical manner to that of SLURPS and is compared
Fig. 5 for SLURPS-C4-OAc and BLURPS-Cl. The solvent response of
BLURPS-Cl is superior to that of SLURPS-C4-OAc. Not only do we
observe a much improved swelling in water and protic solvents (by
a factor 2 or greater), but BLURPS-Cl swells when exposed to
hexane (w2 ml/g). Indeed across the entire polarity scale the
2.3. On bead transformations
We then studied the synthetic utility of the new gel to see if it
was matched the clearly attractive physical properties of BLURPS.
We carried out a conventional functional group interconversion to
deliver the amine terminated analogue of the original gel.
The chloroethyl terminated BLURPS gel was converted to the
N-phthalimide under standard conditions and subsequently the
primary amine was revealed upon exposing the gel to hydrazine at
elevated temperatures (Scheme 5).
The gel-phase 1H and 13C NMR spectra for the starting BLURPS-Cl
gel, BLURPS-N-phthalimide and BLURPS-NH2 are shown in Fig. 7.
Each were produced using routine solution phase acquisition tech-
niques and demonstrate the excellent signal to noise ratios that we
observed previously when analysing the SLURPS-gels. Analysis of the
spectra in sequence proves that each reaction proceeded to comple-
tion which also is consistent with our experience of SLURPS-gels. For
deviation from
a swelling level average has been reduced
substantially (i.e. more balanced response to solvent interactions),
suggesting that BLURPS-Cl has the rather unique ability to interact
with solvents as diverse (and incompatible) as hexane and water.
Indeed BLURBS-Cl out-performs SLURPS-C4-OAc in nonpolar
solvents, in highly polar solvents, and also exhibits a significantly
improved response to diethyl ether, a solvent not only commonly
used in organic synthesis but also one for which SLURPS-gels
showed rather poor swelling characteristics.
OMe
OMe
OH
OAc
i
MeO
MeO
OMe
In order to try to increase the swelling performance of the new
gel further, the cross-linker feed was varied by synthesising gels
containing 3 mol% or 5 mol% cross-linker (3a, n ¼ 0) respectively for
comparison with BLURBS-Cl which contained 4 mol% XL. At least up
OMe
BLURPS-OAc
BLURPS-OH
Scheme 7. Synthesis of BLURPS-OH. i) MeOH/H2O (3:2 v/v), K2CO3, 89% yield.

2990
B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
Fig. 8. Optical micrographs of individual dry beads of BLURPS-OH and the same bead after swelling in various solvents at room temperature for the stated time.
example, the resonancefor the methylene group alpha tothe chloride
in the starting BLURPS-Cl gel at 43.6 ppm is absent in the spectrum of
the BLURPS-N-phthalimide gel whilst the signals for the aromatic
protons of the phthalimide moiety (7.87e7.72 ppm) and associated
13C resonances (168.0,133.8,132.1, 123.2 ppm) are clearly resolved in
the 1H and 13C NMR spectra of the product. The complete removal of
the phthalimide protecting group by action of hydrazine was
confirmed by the absence of all corresponding signals from the
proton spectra of the final BLURPS-NH2 product.
To complete our synthetic investigations into the utility of BLURPS
based beads, the synthesis of an alcohol functionalised variant,
BLURPS-OH was attempted. Thus, the known acetylated vinyl ether 7
was subjected to suspension polymerisation with methoxy vinyl
ether 5 and divinyl ether 3a (Scheme 6) under the conditions estab-
lished during the synthesis of BLURPS-Cl, subsequent removal of the
acetyl group under basic conditions furnished the desired hydroxyl
functionalised gel, BLURPS-OH in 89% yield (Scheme 7). Complete
deprotection of the hydroxyl group was readily verified by IR spec-
troscopy (loss of the carbonyl signal at 1734 cm-1) and by 1H NMR
spectroscopy (loss of the methyl signal at 4.05 ppm).
The solvent compatibility of BLURPS-OH could be readily
demonstrated by subjecting a single bead to an excess of solvent
whilst observing them in real time under an optical microscope.
Fig. 8 shows four isolated beads of dry BLURPS-OH and an image of
the same bead after up to 2 min in contact with solvents of varying
polarity. It can be seen that even within this short timescale,
BLURPS-OH beads typically double in diameter (4 fold increase in
volume) in solvents as diverse as water and toluene.
Encouraged by the outcome of this preliminary set of chemical
transformations, with a performance comparable to the excellent
solid-phase synthesis properties of SLURPS, we are now evaluating
the new gels in multi-step transformations including peptide
synthesis.
scale. We significantly improved upon the solvent compatibility of
the original SLURPS-gel not only by increasing the range of solvents
in which the support swells well in but also by obtaining a more
balanced swelling response across the solvent polarity scale
(hexane to water). As BLURPS-Cl can be prepared entirely from
commercially available monomers this establishes a synthetically
shortened entry to functionalised varieties of this support with
common linker units as a generic and economical solid support
platform. Additionally, by carrying out a short, on bead set of
chemical transformations we have shown that the new BLURPS-
gels have retained the high performance levels of the progenital
SLURPS-gels and thus represent a significant advance in the quest
for a truly universal solid support.
4. Experimental
Nuclear magnetic resonance (NMR) spectra were acquired on
a Varian 400 spectrometer operating at 400 MHz and 100 MHz for
proton and carbon spectra respectively. All signals are quoted in
parts per million (ppm) referenced to the residual protic solvent
signal as internal standard (CDCl3, 1H 7.26 ppm, 13C 77.0 ppm). The
multiplicities of the signals have been abbreviated as follows: (s)-
singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet. Infrared
spectra were measured with a Mattson Satellite 3000 FTIR spec-
trometer. Spectra were obtained from either a thin film (small
molecules) or from CHCl3 swollen beads (polymer gels) held
between two KBr discs. The values obtained are quoted in wave-
numbers (cm-1). Particle size distributions were acquired on
a Mastersizer Model 2000 Hydro (Malvern Ltd., Malvern, U.K.)
using water as dispersant.
All non-fluorinated reagents were bought from commercial
suppliers, either Sigma Aldrich, Lancaster Synthesis, Avocado or
Fisher Scientific, had purities greater than 97% and were used
without further purification. The surfactant used in this work was
sourced from 3M (FC-4430). FC-4430 is a combination of fluo-
roaliphatic polymeric esters (85e95 wt%), a polyether polymer
(5e10 wt%),1-methyl-2-pyrrolidinone (1e2 wt%), toluene (<1 wt%)
and 2-propenoic acid, 2-(methyl(nonafluorobutyl) sulfonyl)amino)
ethyl ester (0e0.5 wt%). DMSO and CH2Cl2 were distilled from CaH2
prior to use. Anhydrous DMF was purchased from Sigma Aldrich
and used as received. Perfluorohexane was purchased from Fluo-
rochem and used as received.
3. Conclusions
We have shown how our original SLURPS-gels can be readily
synthesized on gram scale quantities in a beaded form which is
convenient for manual manipulation during solid-supported
synthesis. We have carried out optimization of the physical prop-
erties of the beaded gels by altering both the constituent monomers
and the cross-linking ratio to deliver a gel that exhibits uniquely
excellent swelling properties across the entire solvent polarity

B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
2991
All reactions were carried out oven dried (120 ꢀC) glassware,
cooled under nitrogen. Reaction temperatures refer to that of the
external medium either an oil or ice bath, except for the bead
synthesis where temperatures refer to the internal reaction
temperature. During bead synthesis, the emulsion was maintained
using a metal three blade 25 mm diameter propeller with a metal
shaft driven by an IKA RW 20 digital overhead stirrer at the speed
specified in the relevant experimental.
Perfluorohexane (100 mL) was added and the solution stirred at
800 rpm whilst being cooled to ꢁ78 ꢀC (approx. 15 min) over which
time the reaction took on a milky appearance. A solution of BF3
diethyletherate (0.12 mL) in CH2BrCl (1.9 mL) was added dropwise
down the shaft of the stirring rod. After 30 min the acetone/cardice
bath was lowered and the reaction allowed to warm to ꢁ30 ꢀC over
25 min during which time small spheres appeared in the suspen-
sion. The temperature was carefully maintained around ꢁ30 ꢀC for
1 h then at ꢁ20 ꢀC for 40 min before the temperature was allowed
to rise to ꢁ10 ꢀC and quenched with an ammonia solution (33% NH3
in H2O, 2 mL) and allowed to warm to ambient temperature. The
colourless spheres were collected by vacuum filtration (Büchner
funnel and filter paper) then washed sequentially with methanol,
THF, ether (2 ꢂ 100 mL of each) and dried under vacuum overnight
to give BLURPS-Cl as sticky colourless spheres 7.37 g (74%). 1H
4.1. Synthesis of methoxyethyl vinyl ether (4)
MeI (55.5 mL, 892 mmol) was added to a stirring slurry of eth-
yleneglycol vinyl ether (40.0 mL, 446 mmol) and KOH (27.5 g,
491 mmol) at 0 ꢀC. After 30 min the ice bath was removed and the
reaction stirred at room temperature for 3 h before water (50 mL)
was added. After stirring for a further 30 min the organic phase was
separated and washed with water (50 mL) and brine (50 mL), then
dried over MgSO4, and the solvents removed on a rotary evaporator
at r.t. Distillation under reduced pressure gave the title compound
(400 MHz, CDCl3)
2.00e1.10 (br, 1.91, 1.63, 1.26, 1.16, 0.30H); 13C (100 MHz, CDCl3)
74.4e73.7, 72.5e71.9, 70.5, 68.9e67.7, 59.1e58.6, 43.6,
d
¼ 3.89e3.20 (br, 3.67, 3.64, 3.53, 3.38, 1H),
d
¼
41.3e40.6, 40.0e38.7. IR (CHCl3) vmax: 3017, 2939, 2871, 1478, 1448,
(32.8 g, 72%).1H (400 MHz, CDCl3)
4.18 (dd, J ¼ 2.2, 14.3, 1H), 4.00 (dd, J ¼ 2.1, 6.8, 1H), 3.83e3.81 (m,
2H), 3.63e3.61 (m, 2H), 3.40 (s, 3H); 13C (100 MHz, CDCl3)
d
¼ 6.49 (dd, J ¼ 6.8, 14.3, 1H),
1376, 1216, 1113, 755, 668.
d
¼ 151.5,
4.4. Synthesis of BLURPS-N-phthalimide
86.4, 70.6, 66.8, 58.9; IR (neat) nmax: 2986, 2817, 1622, 1455, 1397,
1363, 1321, 1293, 1293, 1242, 1204, 1128, 1099, 1039, 966, 848, 820,
To a slowly stirring suspension of BLURPS-Cl (5.30 g, 5.3 mmol)
in DMF (100 mL) was added potassium phthalimide (4.90 g,
26.5 mmol) and KI (176 mg, 1.06 mmol). The suspension was stirred
at 100 ꢀC for 19 h. After cooling to r.t. the salts were dissolved by
adding MeOH (approx. 100 mL) and the yellowish beads collected
by filtration and washed with MeOH, THF, Et2O (2 ꢂ 150 mL of each)
to give BLURPS-N-phthalimide (4.47 g, 82%) as yellow beads. 1H
702; HRMS (CI with NH3) calc. for C5H14NO2
found ¼ 120.1025.
¼
120.1025,
4.2. Beaded SLURPS-C4-OAc (2% XL)
An oven dried 250 mL 3 neck round bottom flask was charged
with FC-4430 (800 mg). A three blade 25 mm propeller from an
overhead stirrer was inserted and the flask flushed with nitrogen.
After 30 min CH2BrCl (10.0 mL), 4-acetoxybutyl vinyl ether (1.58 g,
10.0 mmol), methoxybutyl vinyl ether (7.95 g, 61.1 mmol) and 1,4-
butanediol divinyl ether (0.206 mL, 1.42 mmol) were added and
stirred (400 rpm) at room temperature for 5 min. Perfluorohexane
(100 mL) was added and the solution stirred at 800 rpm whilst
being cooled to ꢁ78 ꢀC (approx. 30 min) over which time the
reaction took on a milky appearance. A solution of BF3 dieth-
yletherate (0.15 mL) in CH2BrCl (1.8 mL) was added dropwise down
the shaft of the stirring rod. After 30 min the acetone/cardice bath
was lowered and the reaction allowed to warm to ꢁ40 ꢀC over
15 min and the reaction maintained at this temperature for 70 min,
warmed to ꢁ30 ꢀC for 60 min then held at ꢁ20 ꢀC for 20 min. The
reaction was quenched at ꢁ10 ꢀC (33% NH3 in H2O, 10 mL) whilst
warming to ambient temperature. The spheres were collected by
vacuum filtration (Büchner funnel and filter paper) then washed
sequentially with methanol, acetonitrile, acetone, tetrahydrofuran
and ether (2 ꢂ 50 mL of each) and dried under vacuum (at r.t.)
overnight to give SLURPS-C4-OAc as sticky colourless spheres 7.64 g
(400 MHz, CDCl3)
d
¼ 7.87e7.75 (br, 1H), 3.70e2.90 (br, 3.60, 3.50,
3.37, 20H), 2.07e0.95 (1.92, 1.57, 1.16, 5.25H); 13C (100 MHz, CDCl3)
d
¼ 168.0, 133.8, 132.1, 123.2, 74.1, 68.1, 68.8e67.4, 58.8, 41.4e40.7,
39.5e39.2, 38.1; IR (CHCl3) vmax: 3025, 2873, 1775, 1711, 1615, 1520,
1450, 1393, 1214, 1130, 1034, 928, 849, 789, 671, 626.
4.5. Synthesis of BLURPS-NH2
Hydrazine monohydrate (0.43 mL, 9.0 mmol) was added
BLURPS-N-phthalimide (3.00 g, 2.98 mmol) in EtOH (60 mL), and
heated under reflux for 18 h. After cooling to r.t. the slightly yellow
spheres were collected by vacuum filtration and washed with EtOH,
THF, and Et2O (2 ꢂ 50 mL each) followed by drying under vacuum
to give BLURPS-NH2 (2.80 g, 94%) as yellow spheres. 1H (400 MHz,
CDCl3)
CDCl3)
d
¼ 4.10e2.80 (br, 0.8H), 2.50e1.10 (br, 0.2H); 13C (100 MHz,
¼ 74.1, 72.3, 68.2e67.5, 58.9, 41.5, 40.9, 39.4; IR (CHCl3)
d
vmax ¼ 3479, 3387, 3041, 2824, 1654, 1600, 1519, 1454, 1397, 1217,
1041, 928, 774, 627.
4.6. Synthesis of 2-acetoxyethyl vinyl ether (7)
(76%). 1H (400 MHz, CDCl3)
30H), 2.10e0.90 (2.04, 1.78, 1.59, 1.55, 0.93, 25H); 13C (400 MHz,
CDCl3)
d
¼ 4.10e2.90 (4.06, 3.64, 3.36, 3.30,
To a stirring solution of 1,2-ethanediol vinyl ether (25.0 mL,
279 mmol) in AcOAc (171 mL, 1.81 mol) at 0 ꢀC was added Et3N
(43.1 mL, 419 mmol) and DMAP (1.70 g, 14.0 mmol). The reaction
was stirred at 0 ꢀC for 1 h then allowed to warm to room temper-
ature and stirred for 18 h. The reaction mixture was poured into
a 2 L beaker containing ice (1.0 kg) and ether (300 mL) and stirred
whilst solid Na2CO3 was added until the aqueous layer was at pH
8e9 and no more bubbling was seen. The organic layer was sepa-
rated and the aqueous layer extracted with ether (3 ꢂ 250 mL). All
the combined organic layers were then washed with brine
(2 ꢂ 150 mL), dried over MgSO4, filtered and the solvent removed
on a rotary evaporator. The product was isolated via vacuum
distillation (b.p. 37e44 ꢀC, water pump vacuum) to give the title
compound as a colourless oil (28.9 g, 80%). 1H (400 MHz, CDCl3)
d
¼ 170.1, 73.8, 72.6, 68.6, 64.4, 58.6, 41.5, 39.5, 27.2, 26.6,
25.8, 21.0; IR (CHCl3) nmax ¼ 3018, 2928, 2869, 2830, 1731, 1518,
1475, 1447, 1387, 1261, 1115, 352, 757, 668, 626.
4.3. Synthesis of BLURPS-Cl
A 250 mL 3 neck round bottom flask was charged with FC-4430
(500 mg). A three blade 25 mm propeller from an overhead stirrer
was inserted and the flask flushed with nitrogen. After 30 min
CH2BrCl (10.0 mL), 2-chloroethyl vinyl ether (1.02 g, 0.97 mL,
10.0 mmol), methoxyethyl vinyl ether (8.58 g, 80.9 mmol) and 1,2-
divinyl ethylene glycol (0.432 g, 0.472 mL, 3.79 mmol) were added
and stirred (400 rpm) at room temperature for
5 min.

2992
B.W. Greenland et al. / Polymer 51 (2010) 2984e2992
d
¼ 6.46 (dd, J ¼ 6.8, 14.4, 1H), 4.31e4.29 (m, 2H), 4.19 (dd, J ¼ 2.3,
14.3, 1H), 4.04 (dd, J ¼ 2.3, 6.8, 1H), 3.88e3.87 (m, 2H), 2.09 (s, 3H);
13C (100 MHz, CDCl3)
The procedure for the volumetric measurement is as follows.
Dry polymer beads (of an equivalent volume of approx. 0.1 ml) were
placed in a graduated plastic syringe (1 ml) and weighed.
d
¼ 171.0, 151.4, 87.1, 65.7, 62.6, 20.9; IR (neat)
vmax: 2959, 2937, 2881, 1743, 1620, 1457, 1374, 1323, 1237, 1200,
1123, 1061, 1007, 983, 825, 639, 605; HRMS (CI with NH3) calc for
C6H14NO3 ¼ 148.0974, found ¼ 148.0975.
A continuous flow of solvent was passed through the syringe at
a rate of approx.1 ml/min, while the polymer beads started to swell.
After 10e30 min (depending on the swelling response of the gels by
visual inspection), interrupted by occasional gentle agitation of the
polymer gel with a thin metal rod, a reading was taken after gently
squeezing most of the excess (interstitial) solvent from the swollen
gel beads using a plunger. This process was then repeated with
another solvent. The solvents used and the sequence in which they
were measured is given in Fig. 6 starting from one end of the
solvent scale, usually water, and arrive back at water by following
the sequence in reverse order. The experimental error of the
swelling values is ꢃ0.5 ml/g. The benefit of the volumetric method
is the relative speed with which it can be carried out in providing
a trend in swelling behaviour for the polymer gels. It is not
a substitute to the gravimetric method [20] to obtain accurate
equilibrium swelling values.
4.7. Synthesis of BLURPS-OAc
An oven dried 250 mL 3 neck round bottom flask was charged
with FC-4430 (400 mg). A three blade 25 mm propeller from an
overhead stirrer was inserted and the flask flushed with nitrogen.
After 30 min CH2BrCl (8.0 mL), 2-acetoxyethyl vinyl ether (1.04 g,
8.00 mmol), methoxyethyl vinyl ether (7.30 g, 71.2 mmol) and 1,2-
divinyl ethylene glycol (0.40 mL, 0.32 mmol) were added and stirred
(400 rpm) at room temperature for 2 min. Perfluorohexane (80 mL)
was added and the solution stirred at 800 rpmwhilst being cooled to
ꢁ78 ꢀC over which time the reaction took on a milky appearance.
A solution of BF3 diethyletherate (0.090 mL) in CH2BrCl (2.0 mL) was
added dropwise down the shaft of the stirring rod. After 30 min the
acetone/cardice bath was lowered and the reaction was allowed to
warm to ꢁ35 ꢀC over 25 min during which time small spheres
appeared in the suspension. The temperature was carefully main-
tained between ꢁ35 ꢀC and ꢁ40 ꢀC for 1 h then at ꢁ30 ꢀC for 10 min
and finally allowed to rise to ꢁ12 ꢀC over 7 min. At this temperature
spheres collected around the outside of the flask began to yellow
and the reaction was quenched with ammonia solution (33% NH3 in
H2O, 2 mL) whilst the reaction was allowed to warm to ambient
temperature. The spheres were collected by vacuum filtration
(Büchner funnel and filter paper) then washed sequentially with
methanol, acetonitrile, acetone, tetrahydrofuran and ether
(2 ꢂ 20 mL of each) and dried under vacuum overnight to give
BLURPS-OAc as sticky colourless spheres 6.70 g (77%). 1H (400 MHz,
Acknowledgements
Financial support for this project from the Department of
Chemistry, Imperial College London (Teaching Assistantship for G.
C.), CVCP (Committee of Vice-Chancellors and Principals) (ORS
(Overseas Research Students) Award for G.C.), and Avecia Ltd. is
gratefully acknowledged. We also thank the EPSRC for contributing
to the funding of this work (Grant GR/N12084/01).
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BLURPS-Ac (5.00 g) was added to a stirring (magnetic stirrer)
solution of MeOH (75 mL), H2O (50 mL) and K2CO3 (5.00 g). After
4 h the reaction was filtered and washed sequentially with MeOH/
H2O (3:2 v/v) (2 ꢂ 50 mL), MeCN (2 ꢂ 50 mL), THF (2 ꢂ 50 mL), and
ether (2 ꢂ 50 mL). The solid was dried under vacuum at room
temperature to constant weight to give of BLURPS-OH (4.42 g, 89%).
1H (400 MHz, CDCl3)
(100 MHz, CDCl3)
d
¼ 4.0e2.2 (br, 0.8H), 2.1e1.0 (br, 0.25H); 13
C
d
¼ 74.1, 72.3, 70.5, 68.2, 62.0, 58.9, 40.9, 39.5. IR
(neat) vmax ¼ 3447, 3011, 2926, 2827, 1625, 1603, 1520, 1454, 1384,
1218, 1119, 1033, 928, 849, 771, 672, 626.
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4.9. Determination of equilibrium swelling values
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Both gravimetric and volumetric determinations of the degree
of swelling have been carried out. The gravimetric procedure has
been described in detail elsewhere [20].