Merrifield resin-supported chain transfer agents, precursors for RAFT polymerization

Article abstract of DOI:10.1021/ol051078t

(Chemical Equation Presented) The modification of Merrifield resins to form chain transfer agent (CTA) precursors for reversible addition fragmentation chain transfer (RAFT) polymerization is investigated. A series of CTA precursor resins were prepared an

Full text of DOI:10.1021/ol051078t

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3449-3452
Merrifield Resin-Supported Chain
Transfer Agents, Precursors for RAFT
Polymerization
Pittaya Takolpuckdee, Craig A. Mars, and Se´bastien Perrier*
Department of Colour and Polymer Chemistry, UniVersity of Leeds, LS2 9JT, UK
s.perrier@leeds.ac.uk
Received May 10, 2005
ABSTRACT
The modification of Merrifield resins to form chain transfer agent (CTA) precursors for reversible addition fragmentation chain transfer (RAFT)
polymerization is investigated. A series of CTA precursor resins were prepared and characterized by FTIR and elemental analysis (EA).
Reversible addition chain transfer (RAFT) polymerization
is among the most versatile of all the controlled/living radical
polymerization techniques used to date due to its compat-
ibility with a wide range of monomers and reaction condi-
tions.1 The RAFT polymerization process and chain transfer
agents (CTAs) used have been extensively studied and
prepared over the past few years.2 However, the process is
not industrially viable due to the presence of impurities
trapped in the final polymer, including uncontrolled poly-
meric chains, monomer, and unrecoverable CTA. One of the
most successful methods for removing a catalyst from a
reaction is to attach it to a solid support.3 Among the range
of solid supports currently available, resins are one of the
most commonly used due to their commercial accessibility,
with a variety of end group functionalities and loadings, and
solvent resistance compared to other solid supports.4 There
are a number of commercially available resins, including
Merrifield,5 Wang,6 and JandaJel,7 all of which have been
used for combinatorial chemistry and solid-phase (supported)
organic syntheses.8 Several solid-supported CTAs have been
reported previously, but all are linked to the support via the
leaving and reinitiating group (R group)9 of the thiocarbonyl-
thio compound (Scheme 1), which results in the final polymer
(3) (a) Utting, K. A.; Macquarrie, D. J. New J. Chem. 2000, 24, 591. (b)
Chinchilla, R.; Mazon, P.; Najera, C. AdV. Synth. Catal. 2004, 346, 1186.
(c) Green, S. D.; Monti, C.; Jackson, R. F. W.; Anson, M. S.; Macdonald,
S. J. F. J. Chem. Soc., Chem. Commun. 2001, 2594.
(4) Vaino, A. R.; Janda, K. D. J. Comb. Chem. 2000, 2, 579.
(5) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(6) Sieber, P. Tetrahedron Lett. 1987, 28, 6147.
* Corresponding author. Tel: +44 113 343 2932. Fax: +44 113 343
2947.
(1) Le, T. P.; Moad, G.; Rizzardo, E.; Thang, S. H. PCT Int. Appl. WO
9801478 A1 980115, 1998.
(7) Brummer, O.; Clapham, B.; Janda, K. D. Tetrahedron Lett. 2001,
42, 2257.
(8) (a) Horton, J. R.; Stamp, L. M.; Routledge, A. Tetrahedron Lett.
2000, 41, 9181. (b) Honigfort, M. E.; Brittain, W. J. Macromolecules 2003,
36, 3111. (c) Slough, G. A.; Krchnak, V.; Helquist, P.; Canham, S. M.
Org. Lett. 2004, 6, 2909.
(9) (a) Quinn, J. F.; Chaplin, R. P.; Davis, T. P. J. Polym. Sci., Part A:
Polym. Chem. 2002, 40, 2956. (b) Barner, L. Aust. J. Chem. 2003, 56, 1091.
(c) Barner, L.; Li, C.; Hao, X.; Stenzel, M. H.; Barner-Kowollik, C.; Davis,
T. P. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 5067. (d) Dublanchet,
A.; Lusinchi, M.; Zard, S. M. Tetrahedron 2002, 58, 5715.
(2) (a) Chiefari, J.; Chong, Y. K.; Ercole, F.; Krstina, J.; Jeffery, J.; Le,
T. P.; Mayadunne, R. T. A.; Meijs, G. F.; Moad, C. L.; Moad, G.; Rizzardo,
E.; Thang, S. H. Macromolecules 1998, 31, 5559. (b) Delduc, P.; Tailhan,
C.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 1988, 308. (c) Barner-
Kowollik, C.; Davis, T. P.; Heuts, J. P. A.; Stenzel, M. H.; Vana, P.;
Whittaker, M. J. Polym. Sci. Part A: Polym. Chem. 2003, 41, 365. (d)
Controlled/LiVing Radical Polymerization. Progress in ATRP, NMP, and
RAFT; Matyjaszewski, K., Ed.; ACS Symposium Series 768; American
Chemical Society: Washington, DC, 2000.
10.1021/ol051078t CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/12/2005

analyses allowed us to quantify the amount of sulfur
introduced on the support, and we deduced the percentage
substitution of Cl by thiocarbonyl-thio group (40% substitu-
tion from S content).12
Scheme 1. Generic Structure of RAFT Chain Transfer Agents
In addition to the synthesis of a Merrifield resin-supported
MCPDB, a Merrifield resin-supported cyanoisopropyl
dithiobenzoate (CPDB)2b,11 analogue, Mer-CPDB, was also
prepared (see Scheme 2). The reaction was similar to that
of Mer-MCPDB, with the methyl-R-bromophenylacetate-
substituted by R-bromoisobutyronitrile13 to give the corre-
sponding Mer-CPDB, which was characterized by FT-IR and
EA. This new compound allowed us to quantify the conver-
sion from thiocarbonyl-thio salt to chain transfer agent by
EA, by comparing the percentage substitution based on N
content to S content. The conversion to the salt was assessed
to be 67% (S content),12 while the conversion to the product
(N content) was much lower (10%). This low conversion
was attributed to the difficulty for the reactants to diffuse to
the reactive sites on the resin, due to the differences in
swelling of the unreacted resin, the dithiobenzoate salt resin,
and the final product.14 Although the results indicated that
both the Mer-MCPDB and Mer-CPDB had been formed, the
carbon/nitrogen to sulfur content from elemental analysis was
not consistent with complete conversion of the dithiobenzoate
salt to the corresponding supported CTA. We therefore
concluded that the S content established from elemental
analysis was not representative of the CTA content on the
resin and were unable to quantify the amount of supported
chain transfer agent.
being attached to the solid support. We report in this
communication the first known immobilized thiocarbonyl-
thio compounds attached to a resin though the radical
stabilizing group (Z group).
We initially attempted the synthesis of a Merrifield resin-
supported analogue (Mer-MCPDB) of the previously reported
S-methoxycarbonylphenylmethyl dithiobenzoate (MCPDB),10
shown in Scheme 2.
Scheme 2. Schematic Representation of the Synthesis of
Merrifield Resin-Supported Dithiobenzoate Derivatives
To overcome both the synthetic and analytical problems
resulting from the stepwise synthesis of the on-the-solid
support, we designed a second synthetic approach, which
involved the preparation of the thiocarbonylthio ester,
followed by attachment of the CTA to the resin. Three
different trithiocarbonate CTAs were synthesized, S-meth-
oxycarbonylphenylmethyl 2-hydroxyethyltrithiocarbonate
(MCPHT), 3-(methoxycarbonylphenylmethylsulfanylthio-
carbonylsulfanyl) propionic acid (MPPA), and 3-(benzyl-
sulfanylthiocarbonylsulfanyl) propionic acid (BSPA).15 Note
that in this case, the CTAs belong to the family of
trithioesters, which have been widely used to mediate RAFT
polymerization.1
The two-step synthesis involves the formation of the
sodium dithiobenzoate salt11 on Merrifield resin via the
reaction of the resin with sodium methoxide and elemental
sulfur. The sodium dithiobenzoate salt was then converted
to (Mer-MCPDB) by the addition of methyl-R-bromo-
phenylacetate.10 The resin was purified by washing with
copious amounts of a range of solvents to remove any
unreacted starting reagents, byproducts, and salts. Resin-
supported compounds are usually characterized by infrared
and elemental analysis (EA).8 In our case, the FT-IR of the
final product showed the expected stretches characteristic
of CdO at 1720 cm-1 and C-O at 1277 cm-1. Elemental
MCPHT was synthesized from 2-mercaptoethanol in the
solution of potassium hydroxide and followed by the addition
of carbon disulfide at room temperature. The solution was
stirred for 5 h; then, methyl-R-bromophenylacetate was
added, and the reaction was heated to 80 °C for 12 h (see
Scheme 3).
(10) (a) Perrier, S.; Takolpuckdee, P.; Westwood, J.; Lewis, D. M.
Macromolecules 2004, 37, 2709. (b) Takolpuckdee, P.; Westwood, J.; Lewis,
D. M.; Perrier, S. Macromol. Symp. 2004, 216, 23.
(11) Perrier, S.; Barner-Kowollik, C.; Quinn, J. F.; Vana, P.; Davis, T.
P. Macromolecules 2002, 35, 8300.
MPPA was prepared from the potassium salt of 3-mer-
captopropionic acid with an excess of carbon disulfide,13
followed by the addition of methyl-R-bromophenylacetate.
(12) Calculated using the following equation:
s × Ms
Stheo (%) )
× 100
(13) Couvreur, P.; Bruylants, A. J. Org. Chem. 1953, 18, 501.
(14) See Supporting Information.
mMer - nCl × (MCl + 2MH) + nCl × Mthio
where Stheo (%) is the theoretical sulfur content of the resin in weight %, s
is the number of sulfur atoms per thiocarbonates, Ms is the molar mass of
sulfur, mMer is the mass of the Merrifield resin used for the synthesis, nCl
is the number of moles of chlorine in the resin, MCl is the molar mass of
chlorine, MH is the molar mass of hydrogen, and Mthio is the molar mass of
the thiocarbonate substituting the chlorine atom.
(15) (a) Stenzel, M. H.; Davis, T. P. J. Polym. Sci., Part A: Polym.
Chem. 2002, 40, 4498. (b) Jesberger, M.; Barner, L.; Stenzel, M. H.;
Malmstro¨m, E.; Davis, T. P.; Barner-Kowollik, C. J. Polym. Sci., Part A:
Polym. Chem. 2003, 41, 3847. (c) Stenzel, M. H.; Davis, T. P.; Fane, A. G.
J. Mater. Chem. 2003, 13, 2090. (d) Barner, L.; Barner-Kowollik, C.; Davis,
T. P.; Stenzel, M. H. Aust. J. Chem. 2004, 57, 19.
3450
Org. Lett., Vol. 7, No. 16, 2005

The modification of the chloromethylphenyl group of
Merrifield resin with MCPHT was achieved by the addition
of MCPHT to a suspension of Merrifield resin in tetra-
hydrofuran in the presence of triethylamine and heated to
reflux for 12 h. The solid was filtered and washed extensively
as previously reported to give a light yellow solid material.
The product was also characterized by FT-IR and EA (16%
conversion of the active sites12).
Scheme 3. Preparation Methodology of
S-Methoxycarbonyl-phenylmethyl 2-Hydroxyethyl
Trithiocarbonate (MCPHT)
Scheme 5. Schematic Representation of the Synthesis of
Merrifield Resin-Supported Trithiocarbonate Derivatives
The product was isolated by acidification of the solution with
hydrochloric acid to give a yellow solid. BSPA was
synthesized using the same procedure as MPPA, but with
the addition of benzyl bromide in place of methyl-R-
bromophenylacetate (see Scheme 4).
Scheme 4. Preparation Methodology of (a)
3-(Methoxycarbonyl phenylmethylsulfanylthiocarbonylsulfanyl)
Propionic Acid (MPPA) and (b)
3-(Benzylsulfanylthiocarbonylsulfanyl) Propionic Acid (BSPA)
In RAFT polymerization mediated by these supported
CTAs, the polymeric chains grow away from the resin
support, before reacting back on the CdS bond to trigger
the chain transfer reaction.1 A direct outcome of such process
is that the products from termination reactions remain in
solution, while the living chains are attached to the support.
Therefore, supported chain transfer agent offers the great
advantage of allowing separation by filtration between pure
living polymeric chains, which are attached to the support,
from nonliving chains, nonreacted monomers, and other side-
products from the reaction, which remain free in solution.
To illustrate the principle, we used Mer-MCPDB and Mer-
BSPA to mediate the polymerization of methyl acrylate and
styrene (Table 1). All polymerizations were performed in
toluene (1:1 v/v to monomer). After polymerization, the
polymeric chains attached to the beads were recovered by
filtration and cleaved from the support by reaction with an
excess of AIBN at 80 °C in toluene, following a procedure
recently reported by our group.17 The cleaved polymeric
chains were analyzed by size exclusion chromatography.
Table 1 illustrates the results and shows that a variety of
The modification of the chloromethylphenyl group of
Merrifield resin with MPPA and BSPA was achieved by the
addition of MPPA or BSPA to a suspension of Merrifield
resin in tetrahydrofuran in the presence of potassium carbon-
ate and tetra-n-butylammonium iodide and heated to 60 °C
for 12 h.16
The solid was filtered and washed extensively with THF
and then a mixture of water and THF (1:1), H2O, acetone,
toluene, and acetone to give a deep yellow solid material.
The product was characterized by FTIR and EA to confirm
the formation of MPPA and BSPA on the resins (Mer-MPPA
and Mer-BSPA, respectively). Elemental analysis (EA)
shows that the S content in Mer-MPPA and Mer-BSPA is
0.48 and 0.7 mmol/g (equivalent to 68 and 86% conversion
of the active sites12), respectively. Indeed, in this case, the
measured S content is representative of the CTA content on
the resin.
(16) Amsberry, K. L.; Borchardt, R. T. J. Org. Chem. 1990, 55, 5867.
Org. Lett., Vol. 7, No. 16, 2005
3451

with polydispersities ranging from 1.2-1.3. Further work is
being conducted in our laboratories in order to improve the
control over such polymerizations.
Table 1. Examples of Polymers Produced via
Merrifield-Supported RAFT Polymerization
M
n,theob
Acknowledgment. P.T. acknowledges the Royal Thai
Government and Department of Colour and Polymer Chem-
istry, University of Leeds, for their financial support.
c
CTA
monomera
(conversion)
Mn
PDIc
Mer-MCPDBd
Mer-BSPAe
Mer-BSPAe
MA
MA
S
14 800 (69%)
2100 (24%)
2600 (25%)
13 950
1800
2200
1.24
1.21
1.32
Supporting Information Available: All experimental
procedures and analyses data. This material is available free
of charge via the Internet at http://pubs.acs.org.
a MA: methyl acrylate. S: styrene. b Units: g/mol. c Units: g/mol.
Determined by size exclusion chromatography, using THF as an eluent,
toluene as a flow rate marker, and PS as standards. d Ratio of monomer:
CTA:AIBN ) 250:1:0.1. e Ratio of monomer:CTA:AIBN ) 100:1:0.1.
OL051078T
molecular weights can be achieved via RAFT-supported
polymerization mediated by the CTAs reported in this study,
(17) Perrier, S.; Takolpuckdee, P.; Mars, C. A. Macromolecules 2005,
38, 2033.
3452
Org. Lett., Vol. 7, No. 16, 2005