Poly(4-tert-butylstyrene) as a soluble polymer support in homogeneous catalysis

Article abstract of DOI:10.1021/ol034655r

(Matrix presented) Use of soluble poly(4-tert-butylstyrene) (PtBS) as a support in synthesis is demonstrated. These soluble polymers supported catalysts that were used in a monophasic medium. Subsequent separation of the catalysts after reaction was effected either by cooling- or by water-induced liquid/liquid-phase separation. Specific catalysts studied included both phosphine and DMAP nucleophilic catalysts. Low loadings of an azo dye quantified the efficiency of separation and recovery of these catalysts through multiple reaction cycles.

Full text of DOI:10.1021/ol034655r

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2445-2447
Poly(4-tert-butylstyrene) as a Soluble
Polymer Support in Homogeneous
Catalysis
David E. Bergbreiter* and Chunmei Li
Chemistry Department, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
bergbreiter@tamu.edu
Received April 16, 2003
ABSTRACT
Use of soluble poly(4-tert-butylstyrene) (PtBS) as a support in synthesis is demonstrated. These soluble polymers supported catalysts that
were used in a monophasic medium. Subsequent separation of the catalysts after reaction was effected either by cooling- or by water-induced
liquid/liquid-phase separation. Specific catalysts studied included both phosphine and DMAP nucleophilic catalysts. Low loadings of an azo
dye quantified the efficiency of separation and recovery of these catalysts through multiple reaction cycles.
Polymer supports are widely used in catalysis and synthesis.
This chemistry has its origin in the solid-phase peptide
synthesis strategy developed by Merrifield using cross-linked
polystyrene.1,2 Much of the subsequent work has continued
to use similar insoluble polystyrene supports. However,
soluble linear polymers, as well as dendrimers, are gaining
increasing recognition because of their advantages in syn-
thesis and characterization.2-7 These soluble polymers can
have the same separation advantages as insoluble supports
when separation techniques such as membrane filtration,
precipitation, and liquid/liquid-phase separation are used.3
Here we describe a new type of soluble polystyrene support,
poly(4-tert-butylstyrene), and show how catalysts on this
alkylated polystyrene can be used under monophasic condi-
tions but separated in the nonpolar phase of a biphasic solvent
mixture.
Linear polystyrene has been used to support catalysts,
substrates, and reagents.2,4 It is most commonly recovered
by solvent precipitation. Solvent precipitation is a general
way to recover soluble polymers, but the excess solvents
necessary for this process make this a less convenient and
less Green procedure. Poly(4-tert-butylstyrene) (PtBS) is an
alternative to polystyrene that can be prepared by radical
polymerization of a commercial monomer. PtBS has received
limited attention as a polymer support and as a component
in block copolymers.8 However, PtBS homopolymer has not
generally been used as a support, presumably because it
offers no advantages in separation if separation involves
solvent precipitation chemistry. Here we show that the
heptane solubility of PtBS makes it useful in liquid/liquid
biphasic separations. PtBS and other alkylated polystyrenes
are otherwise similar to PS, and such heptane solubility under
biphasic separation conditions is a general strategy for
separation and recovery of species bound to these polystyrene-
like polymers. This possibility has also been noted by Plenio,
(1) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(2) McNamara, C.; Dixon, M. J.; Bradley, M. Chem. ReV. 2002, 102,
3275-3300.
(3) Bergbreiter, D. E. Chem. ReV. 2002, 102, 3345-83.
(4) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002, 102,
3325-3344.
(5) van Heerbeek, R.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek,
J. N. H. Chem. ReV. 2002, 102, 3717-3756.
(6) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33, 546-554.
(7) Vankelecom, I. F. J. Chem. ReV. 2002, 102, 3779-3810.
10.1021/ol034655r CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/13/2003

who has used a cyclohexane as a solvent for a p-methyl-
styrene support.9
Poly(4-tert-butylstyrene) supports were prepared using
radical copolymerization (eq 1). Chloromethyl styrene or dye-
labeled polystyrene were used as comonomers.
focuses on the use of a latent biphasic system using heptane
and ethanol because the nucleophile-catalyzed reactions we
used were most conveniently run at room temperature.
The copolymer obtained in eq 2 was characterized by GPC.
It had an Mn of 23 000 Da and an Mw of 48 000 Da. It was
readily soluble in heptane. Moreover, this dye-labeled poly-
(tert-butylstyrene) was phase selectively soluble in heptane
when another polar phase was present. Specifically, when 2
was first dissolved in heptane and then mixed with an equal
volume of either DMF or 90% aqueous ethanol, a biphasic
mixture formed with a yellow heptane phase. Heating either
of these biphasic solutions to 70 °C produced a monophasic
mixture. Cooling these thermomorphic mixtures of polymer
and solvents back to room temperature reformed the biphasic
solution. UV-visible spectroscopic analysis of the nonpolar
and polar phases of the product biphasic mixture (λmax and
the ꢀ of the dye were 427 nm and 26 000, respectively)
showed no detectable (<0.5%) dye in the aqueous ethanol
phase. The copolymer 2 was also readily separable in a latent
biphasic system. The copolymer 2 dissolved in a miscible
mixture (1:1, vol:vol) of heptane and EtOH. Addition of 10
vol % water produced a biphasic mixture with the dye-
labeled polymer exclusively in the less polar heptane-rich
phase (>99.5% selective solubility).
A cursory examination of other PtBS copolymers suggests
that the separations achieved with the thermomorphic or
latent biphasic strategies described above are general, though
exceptions exist. For example, the catalysts described below
all were successfully recovered in heptane. A copolymer
formed from 4-tert-butylstyrene and vinyl pyridine also was
selectively soluble in heptane under thermomorphic condi-
tions using heptane-aqueous EtOH or heptane-DMF on the
basis of UV-visible analysis using a dye-labeled PtBS.
However, alkylated pyridinium salts of this copolymer were
mainly or exclusively in the DMF (polar) phase under similar
conditions.
The product copolymer was isolated by solvent precipitation
using methanol. In the case of the dye-labeled copolymer 2,
this solvent precipitation was quantitative on the basis of
the absence of dye label in the supernatant.
Solvent precipitation can be used with PtBS, but there is
no advantage to using PtBS over polystyrene if this technique
is used to recover the polymer. Fortunately, two other
techniques are available: thermomorphic separations of a
polar/nonpolar mixed solvent system or a technique we have
termed latent biphasic chemistry.10-15 An alkylated poly-
styrene like poly(tert-butylstyrene) is more useful than
polystyrene in either of these techniques. In both techniques,
the reactions involving the polymer support occur in a
monophasic mixture. Separation occurs in a subsequent
biphasic mixture on the basis of the phase-selective solubility
of an alkylated polystyrene like PtBS in heptane or cyclo-
hexane rather than in a polar organic solvent. Thermomorphic
systems use solvent mixtures that are miscible hot and
biphasic cold. Latent biphasic separations use miscible
solvent mixtures at the cusp of immiscibility to run a
reaction.12-15 In these cases, phase separation occurs at the
end of the reaction by the addition of a small amount of
another solvent or by the addition of some other perturbant.
Either technique can be used with PtBS, but this paper
Poly(4-tert-butylstyrene) copolymers containing nucleo-
philic catalysts or ligands can be prepared by copolymeri-
zation or by modification of 1 (eq 3).
(8) Gravert, D. J.; Datta, A.; Wentworth, P., Jr.; Janda, K. D. J. Am.
Chem. Soc. 1998, 120, 9481-9495.
(9) Datta, A.; Plenio, H. Chem. Commun. 2003, in press.
(10) Bergbreiter, D. E.; Liu, Y.-S.; Osburn, P. L. J. Am. Chem. Soc.
1998, 120, 4251-4252.
(11) Bergbreiter, D. E.; Osburn, P. L.; Frels, J. D. J. Am. Chem. Soc.
2001, 123, 11105-11106.
(12) Bergbreiter, D. E.; Osburn, P. L.; Smith, T.; Li, C.; Frels, J. D. J.
Am. Chem. Soc. 2003, 125, 6254-6260.
(13) Deng, G.-J.; Fan, Q.-H.; Chen, X.-M.; Liu, D.-S.; Chan, A. S. C.
Chem. Commun. 2002, 1570-1571.
(14) Abatjoglou, A. G.; Peterson, R. R.; Bryant, D. R. Chem. Ind. 1996,
68, 133-139 described this process as phase decantation.
(15) Scurto, A. M.; Aki, S. N. V. K.; Brennecke, J. F. J. Am. Chem.
Soc. 2002, 124, 10276-10277.
A triarylphosphine was attached to a poly(4-tert-butylstyrene)
support and then used to catalyze the Michael addition of
2446
Org. Lett., Vol. 5, No. 14, 2003

2-nitropropane to methyl acrylate (eq 4). In this chemistry,
the phosphine oxide was attached to the polymer and
subsequently reduced to the active phosphine catalyst once
the polymer was formed. The nucleophilic polymer-bound
catalyst 3 also included some methyl red-labeled comonomer
that served as a colorimetric tag to facilitate studies of the
extent of recycling of the polymeric catalyst.
cycles of this reaction were 34.3, 60.9, 82.2, 94.6, and 99%.
As was true in thermomorphic systems or in the latent
biphasic chemistry with 5 described above, partitioning of
product into the nonpolar heptane phase produced lower
isolated yields of product in the early cycles. In this case,
we reused catalyst 5 through 20 cycles.
In a nucleophilic Michael reaction, the supported catalyst
3 was first dissolved in heptane. Then, an equal volume of
an ethanol solution of the substrates was added. The resultant
reaction occurred in a homogeneous mixture of ethanol and
heptane. Unlike thermomorphic systems that we studied
earlier, elevated temperatures were not required. After 24 h
at 25 °C, a small amount (<10 vol %) of water was added
to induce phase separation. The product was isolated from
the ethanol phase. UV-visible spectroscopy showed that all
the PtBS-bound catalyst was in the nonpolar heptane-rich
phase, an observation that correlated with a simple visual
inspection of color of the two phases of this latent biphasic
system. Liquid/liquid phase separation then separated this
product phase from the catalyst-containing phase. The
addition of a fresh ethanol solution of nitropropane and
methylacrylate to this heptane solution of the polymer-bound
phosphine catalyst was all that was required for a subsequent
cycle of the catalytic reaction. The isolated yields of Michael
addition product 4 through the first five cycles were 31.5,
56.7, 69.0, 72.5, and 71.1%. As can be seen, the initially
low yield increases with increasing cycle number. This is
because the product has some solubility in heptane. Thus,
the product in the first cycle only represents the product that
partitions into the aqueous ethanol phase. As the cycle
number increases, the heptane phase eventually gets saturated
with the product and the isolated yield from the aqueous
ethanol phase increases. This effect has been noted in other
biphasic systems both by us and others.16 The yields in the
later cycles of this repetitive reaction were similar to those
seen if the same reaction were catalyzed by triphenylphos-
phine.17
Isolation and recycling of the catalyst was achieved using
the procedures described above for the phosphine catalyst.
Yields after the first few cycles were essentially quantitative
(ca. 93% average for each of 20 cycles). Separation of the
polymer from the aqueous ethanol phase was quantitative
as judged by either visual observation or UV-visible
spectroscopic analysis.
To summarize, poly(4-tert-butylstyrene) copolymers are
effective soluble polymer supports that can readily be
recycled as heptane solutions after their use in a homoge-
neous reaction using liquid/liquid biphasic separations. While
some copolymers (e.g., copolymers with alkylpyridinium
groups) are not selectively soluble in alkane solvents,
ongoing work in our group will address this through the
synthesis of even more lipophilic alkylated polystyrene
derivatives.
Acknowledgment. Support of this work by the R. A.
Welch Foundation, the National Science Foundation (CHE-
0010103), and ArQule is gratefully acknowledged. We thank
Professor Plenio of Darmstadt University for sharing with
us some of his group’s preliminary work on novel transition
metal catalysts supported on linear poly(4-methylstyrene).
A second nucleophilic catalyst supported by PtBS is the
polymer-bound (dimethylamino)pyridine analogue we sup-
ported earlier on poly(N-alkylacrylamide)s. The synthesis of
this polymer-bound catalyst is shown in eq 5.
This second example of a nucleophilic catalyst (5) was
used to catalyze formation of a t-Boc derivative of 2,6-
dimethylphenol (eq 6). In this case, the extent of recovery
of the catalyst and the yields of product were directly
comparable to those seen with the thermomorphic systems
we described earlier.18 The isolated yield for the first five
Supporting Information Available: Procedures for the
synthesis of the chloro-methylstyrene-c-poly(4-tert-butyl-
styrene) copolymer, catalyst 3, and catalyst 5. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL034655R
(16) Kollhofer, A.; Plenio, H. Chem. Eur. J. 2003, 9, 1416-1425.
(17) White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 37, 3597-
3600.
(18) Bergbreiter, D. E.; Osburn, P. L.; Li, C. Org. Lett. 2002, 4, 737-
740.
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