Solid-phase synthesis on functionalised fluoropolymer resins. Part 2: Preparation and properties of functional merrifieldtype resins possessing a perfluorinated polymer backbone

Article abstract of DOI:10.1016/S0040-4039(00)00647-X

Monomers α,β,β-trifluorostyrene and 4-methyl-α,β,β- trifluorostyrene were prepared and were copolymerised under free-radical emulsion conditions to give highly stable, well defined lipophilic polymer resins. Benzylic halogenation of the polymer products gave 4-chloromethyl and 4-bromomethyl derivatives which could be elaborated through nucleophilic displacement of halide. The reaction of 4-fluorophenol with the 4- chloromethylated poly(trifluorostyrene) resin was followed by ¹H and ¹⁹F NMR spectroscopy and proceeded more rapidly than for Merrifield resin. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00647-X

Tetrahedron Letters 41 (2000) 4493±4497
Solid-phase synthesis on functionalised ¯uoropolymer resins.
Part 2: Preparation and properties of functional Merri®eld-
type resins possessing a per¯uorinated polymer backbone
Shuyuan Liu, Mahmoud Akhtar and David Gani*
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham B15 2T, UK
Received 1 March 2000; accepted 20 April 2000
Abstract
Monomers a,b,b-tri¯uorostyrene and 4-methyl-a,b,b-tri¯uorostyrene were prepared and were copolymerised
under free-radical emulsion conditions to give highly stable, well de®ned lipophilic polymer resins. Benzylic
halogenation of the polymer products gave 4-chloromethyl and 4-bromomethyl derivatives which could be
elaborated through nucleophilic displacement of halide. The reaction of 4-¯uorophenol with the 4-chloro-
1
methylated poly(tri¯uorostyrene) resin was followed by H and 19F NMR spectroscopy and proceeded
more rapidly than for Merri®eld resin. # 2000 Elsevier Science Ltd. All rights reserved.
Polystyrene (PS) has been the main base polymer of choice in synthetic applications of func-
tionalised polymer supports since the advent of solid-phase (SP) peptide synthesis,1 and the
emergence of combinatorial chemistry.2 Solid-phase organic chemistry now plays an increasingly
important role in drug and catalyst synthesis and o€ers signi®cant advantages over solution-
phase alternatives in several instances.
Increasing the range of synthetic methods accessible to SP protocols and to be able to perform
a larger repertoire of established solution phase chemistry requires the core polymer to be robust
and chemically resilient. Polystyrene su€ers intrinsic limitations associated with its chemical,
mechanical and thermal stabilities, and hence, polystyrene based supports are not suitable for
many applications where harsh conditions are required. Few of the fundamental problems associated
with polystyrene and other polyethylene-based polymers have yet been overcome, but rather
modi®cations to linker groups have been introduced to improve reaction performance.
Fluoropolymers and in particular polytetra¯uoroethylene (PTFE) display outstanding chemical
inertness and heat resistance, and are good candidates for the polymer backbone of resins for
synthesis. In the previous article we showed that while functionalised derivatives of the ¯uoro-
polymer Na®on are robust and chemically resilient, they are not useful in solid-phase organic
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00647-X

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synthesis (SPOS),3 apparently because the per¯uoropolymer side chains cannot solvate in organic
solvents. In order to overcome the lipophobicity problems of per¯uoropolymers, `functionalised
hydrocarbon branched' ¯uoropolymer supports were developed. The ®rst example of which we
describe here is based upon poly(a,b,b-tri¯uorostyrene) (PTFS) (Fig. 1). As an analogue of PS, it
was expected that it would be possible to transfer existing solid phase chemistries to such polymer
supports and also signi®cantly extend the range of possible reactions and applications, many of
which currently are dicult on conventional supports.
Figure 1. Structure of a hydrocarbon branched resin based on poly(tri¯uorostyrene)
a,b,b-Tri¯uorostyrene (TFS) 4 was ®rst synthesised by Cohen in 19494 and was successfully
polymerised by Prober in 1953.5 Extensive studies on the synthesis of TFS based polymers and
copolymers have been reported,6 and the stability of PTFS based polymers has been utilised in
ion exchange applications where sulfonated PTFS systems have been developed. Here, the func-
tionality was either introduced before7 or after6c,8 polymerisation, and, in principle, either of these
two strategies could be employed to synthesise 1 or 2. The ®rst approach mirrors conventional
routes to functionalised pre-formed polystyrene,1 and involves a Friedel±Crafts type `halogeno-
methylation'. This reaction was expected to be dicult for PTFS and to give meta substitution,
due to the electron-withdrawing nature of the backbone, as was observed by Hodgdon in the
sulfonation of PTFS.8a
This approach gives random functionalisation and might present problems with site distribution,
regio-isomerisation and additional crosslinking-bridge side reactions and was therefore not pursued
further. The alternative site-directed approach, to introduce functional precursors by means of
co-polymerisation, Scheme 1, was considered, and was expected to lead to well de®ned site
distribution and uniform para substitution. Furthermore, it was expected that para-methyl
groups (as reactive precursors) could be introduced from para-methyl-a,b,b-tri¯uorostyrene
(MTFS) comonomer 5 and then be converted to chloromethyl and bromomethyl groups through
benzylic halogenation reactions of copolymer 1 after copolymerisation.
Of the methods described for the synthesis of a,b,b-tri¯uorostyrene derivatives,6c,9 Burton's
method10 is accepted as the most useful.6d,7,11 Accordingly, tri¯uorovinyl bromide was reacted
with activated zinc dust and the resulting tri¯uorovinyl zinc bromide was cross coupled with
either iodobenzene or 4-iodotoluene in the presence of palladium(0) to give TFS 4 and MTFS 5,
Scheme 1.10
Both radical and ionic polymerisation of TFS are known to be dicult.6,12 Due to the large size
of ¯uorine atoms, relative to hydrogen, TFS is more than four times less reactive towards free
radical (trichloromethyl radical) attack than styrene.13 A 2+2 cycloaddition which occurs at
higher temperatures also competes with polymerisation,5,6c,11,14 resulting in low molecular weight
PTFS under normal suspension polymerisation conditions.6 Thus emulsion polymerization at low
temperature, using high concentrations of emulsi®er, appeared be the only useful method to
synthesise relatively high-molecular PTFS.5 7,15 When polymerisations under such conditions5

4495
Scheme 1. Reagents and conditions. (i) Zinc dust, DMF, 50ꢀC, 3 h; (ii) iodobenzene (for 4) or 4-iodotoluene (for 5),
Pd(0)(PPh3)4, DMF, 50ꢀC, 48 h; (iii) K2S4O8, dodecylamine hydrochloride, H2O, 50ꢀC, 72 h; (iv) BTMA ICI4, AIBN,
Ph-CF3, 85ꢀC, 72 h to give 2. NBS, C6H6, sunlamp light, 0.5±8 h to give 3; (v) 4-¯uorophenol, NaH, DMF, 0ꢀC, 1 h
then 2, rt, 3 h
were carried out poly(a,b,b-tri¯uorostyrene) PTFS and TFS-MTFS copolymer 1 (Scheme 1) were
obtained. In the co-polymerisation of TFS 4 and MTFS 5, the incorporation of MTFS in the
para-methyl PTFS copolymer 1 according to microanalytical and 1H NMR spectral data, Fig. 2,
was in excellent accordance with the starting compositions of the two monomers. This result
suggests that TFS and MTFS possess similar reactivity and should give rise to a uniform
distribution.
Figure 2.
Halogenation of the TFS-MTFS copolymer to give functionalisation sites were performed
under a range of conditions.16,17 Benzyltrimethylammonium tetrachloroiodate (BTMA ICl4)17
proved to be most useful in the chlorination of PMTFS to give compound 2 (CMPTFS) (Fig. 2)
and N-bromosuccinimide (NBS)16b,c was useful in bromination of the PMTFS copolymer to give
compound 3 (BMPTFS), Scheme 1.
The PTFS polymers were brittle white solids, of molecular weights in the range of 1Â105 to
5Â105,5 and gave satisfactory elemental analyses. The molecular weights as determined by GPC
are in the range 4Â104 to 3Â106 with up to 2Â104 repeat units and suggest that the polymers
possess high polydispersities. FTIR spectra showed characteristic strong C±F stretching bands

4496
(1077±1272 cm^1). The NMR spectra of the PTFS polymers suggested the construction of the
polymer to be a random event, similar to PS polymers. Multi-signals for the same type of nucleus
suggest the polymer structure is a mixture of isotactic, syndiotactic and heterotactic triads and the
whole skeleton is very sti€.
PTFS polymers are thermally stable and their behaviour is distinctive. Although it was reported
that the glass transition temperature (Tg) of PTFS was 202ꢀC by di€erential scanning calorimetric
(DSC) measurements18 and similar values by calculation,19 our DSC analysis showed that there
were neither observable Tg nor melting points (Tm). The polymer did not start decomposing until
about 350ꢀC. This is not surprising because the backbone and aryl groups of PTFS are very sti€
due to the large size of ¯uorine atoms and the steric hindrance prevents the rotation of the phenyl
group (at glass transition) and along the backbone (at melt). Thus, the resin does not respond to
heating and cooling, hence, it can be used over a wide range of temperatures. The resin was either
soluble or swellable in a range of solvents, including chloroform, DMF, acetone and benzene and
therefore of potential use in liquid phase organic synthesis where reactions occur in homogeneous
solution.20 The insolubility of PTFS resin in solvents, such as methanol, allows precipitation and
therefore makes work-up very simple and easy.
The solubility of PTFS resins in CDCl3 and other solvents, together with the relatively transparent
1H NMR spectrum of PTFS polymer supports (the proton signals occur between 5.2 and 7.5
ppm), o€ers advantages in monitoring multi-step supported syntheses (Fig. 2).
The ability of the functional site in the chloromethyl derivative of PTFS 2 to react with
1
nucleophiles was tested with 4-¯uorophenol (Scheme 1). The -CH2Cl and -CH2O- H NMR
signals in resin-bound form were used directly to estimate the absolute extent of reaction and the
rate of the reaction (Fig. 2). The reaction was complete within 3 h at room temperature as judged
1
by H and 19F NMR spectra. The kinetics of the reaction were examined using real-time in-situ
NMR techniques and were found to be competitive with the rates for Merri®eld resin.
Thus PTFS based resins appear to be ideal for the construction of supported systems and of
potential in organic synthesis.
Acknowledgements
We thank EPSRC and DERA for the ®nancial support on this work, and useful discussions
with Dr. P Coe on the synthesis of TFS.
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