One-pot multistep reactions based on thiolactones: Extending the realm of thiol-ene chemistry in polymer synthesis

Article abstract of DOI:10.1021/ja1098098

The in situ generation of thiols by nucleophilic ring-opening of a thiolactone with amines, followed by a UV-initiated radical thiol-ene reaction in a one-pot fashion, has been evaluated as an accelerated and versatile protocol for the synthesis of several types of polymeric architectures. After elaboration of a model amine-thiol-ene conjugation reaction, a number of routes based on readily available thiolactone-containing structures have been developed to successfully assemble functional, linear polymers and networks via a mild and facile radical photopolymerization process.

Full text of DOI:10.1021/ja1098098

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One-Pot Multistep Reactions Based on Thiolactones: Extending the
Realm of Thiol-Ene Chemistry in Polymer Synthesis
Pieter Espeel, Fabienne Goethals, and Filip E. Du Prez*
Department of Organic Chemistry, Polymer Chemistry Research Group, Ghent University, Krijgslaan 281 S4-bis, B-9000 Ghent,
Belgium
S Supporting Information
b
based on metal-free radical thiol-ene chemistry in order to modify
ABSTRACT: The in situ generation of thiols by nucleo-
philic ring-opening of a thiolactone with amines, followed by
a UV-initiatedradicalthiol-ene reactionina one-pot fashion,
has been evaluated as an accelerated and versatile protocol
for the synthesis of several types of polymeric architectures.
After elaboration of a model amine-thiol-ene conjuga-
tion reaction, a number of routes based on readily available
thiolactone-containing structures have been developed to
successfully assemble functional, linear polymers and networks
via a mild and facile radical photopolymerization process.
or assemble polymeric materials. In addition to the fact that the
commercial availability of thiols as starting materials is rather limited,
thiols usually have an unpleasant smell and might have a poor shelf
life due to oxidation reactions. Therefore it can be advantageous to
generate thiols in situ and convert them in a one-pot process. In a
very recent report on a metal-free two-step approach,11 a dithio-
benzoate at the ω chain end of a polymer obtained via RAFT
(reversible addition-fragmentation chain transfer) was converted
to the corresponding thiol via aminolysis and this thiol acted as a
nucleophile in a subsequent thio-bromo ‘click’ reaction. Others
previously reported the one-pot process that combines aminolysis
of the trithiocarbonate end groups as latent thiols and nucleophilic
Michael addition of the resulting thiols.12
Our investigation was inspired by a decades-old method for
the introduction of sulfhydryl groups in natural proteins.13 This
thiolation of proteins consists of the nucleophilic ring-opening of
the readily available N-acetylhomocysteine thiolactone 1 by the
ε-NH2 groups of lysine residues. We anticipated the ability to
adapt this methodology and combine it with the radical thiol-
ene process in a one-pot fashion as a mild approach for the synthesis
of polymeric architectures starting from stable amine containing
compounds. Although the presented concept (Scheme 1) might
not be broadly applicable due to the reactive nature of amines and
radical species (orthogonality issues), this amine-thiol-ene con-
jugation as a simple, efficient, and modular linking process is con-
sidered to be a relevant extension of the currently quite popular
thiol-ene chemistry, especially in polymer science.
In the first stage of this study, the one-pot two-step sequence
was performed on low-molecular-weight model compounds in
order to investigate the reaction kinetics and to analyze the com-
position of the obtained reaction mixture. Benzylamine 2 was
treated with thiolactone 1 in the presence of 4-dimethylamino-
pyridine (DMAP) as a nucleophilic catalyst. In the initial reaction
mixture, an excess of norbornene (ene-compound) 3 was added
to allow for the subsequent radical thiol-ene reaction. The reac-
tion mixture was irradiated by an external UV-light source, and
2,2-dimethoxy-2-phenyl acetophenone (DMPA) was selected as
an efficient photoinitiator for thiol-ene conjugation.14 Because
of the extremely high reactivity of the norbornene double bond
toward thiyl radicals,9 the first step of the reaction sequence was
considered to be rate-determining. In an online 1H NMR experi-
ment, the consumption of 2 was monitored by the decrease of the
signal of the corresponding benzylic protons. This study pointed
ecently, many organic reactions, generally labeled as ‘click’
R
chemistry and originally developed and applied in the syn-
thesis of low-molecular-weight compounds, infiltrated the tool-
box of synthetic macro- and supramolecular research groups.1
One of the major virtues of the ‘click’ concept has been, since its
introduction in polymer science,2 the paradigm shift toward a
modular construction approach of complex innovative polymeric
architectures.3 In addition to this awareness, the challenge was
taken up to combine these robust, efficient, and orthogonal con-
jugation chemistries, resulting in the development of several ele-
gant one-pot, multistep strategies, enabling the implementation
of accelerated synthetic protocols.4 An important class of one-
pot, multistep reactions is characterized by the fact that all
chemicals initially are mixed and consecutive reactions depend
on each other. For example, a potentially explosive azide can be
generated in situ, starting from the corresponding bromide via
nucleophilic substitution or amine via diazotransfer, and can
subsequently be converted to a triazole via the copper-catalyzed
azide-alkyne cycloaddition (CuAAC) in the same pot.5 So far,
virtually all of these one-pot reaction sequences encompass the
heavily exploited Huisgen CuAAC as the key step. The main
disadvantage of this popular ‘click’ reaction, ruling out many
potential applications, is the presence of complexed copper in the
reaction products. Currently, metal-free methodologies which
fulfill the set of ‘click’ requirements6 are eagerly developed and
evaluated.7 The radical or nucleophilic addition of a thiol to a
double bond (thiol-ene chemistry8-10) has recently been re-
cognized as a valuable metal-free alternative for the CuAAC due
to some inherent ‘click’ characteristics.
As Malkoch et al.4 expressed the need to increase the range of
available ‘click’ reactions that can be achieved without the need of
metal catalysts and to develop libraries of compatible reactions,
our ongoing interest is to develop an efficient one-pot process
Received: November 1, 2010
Published: January 25, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja1098098 J. Am. Chem. Soc. 2011, 133, 1678–1681
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Scheme 1. General Concept of the Investigated Metal-Free
One-Pot Reaction: Nucleophilic Opening of a Thiolactone
(Aminolysis), Followed by a Radical Thiol-Ene Conjugation
Scheme 2. Model Amine-Thiol-Ene Conjugation: One-
Pot Reaction between Benzylamine, N-Acetylhomocysteine
Thiolactone, and Norbornene under UV-Irradiation without
the Use of a Photoinitiator
out that 2 was fully consumed after being in the presence of a
2-fold excess of 1 and 10 mol % of DMAP for 6 h (Figure S1).
Furthermore, thorough analysis of the reaction mixture obtained
after the two-step reaction by LC-MS revealed, in addition to the
presence of the desired compound 4, the formation of side prod-
ucts, originating from the reaction between 2 and radical frag-
ments of DMPA (Figure S2). However, using optimal conditions
(no photoinitiator) and after a straightforward chromatographic
purification, the model reaction yielded the conjugation com-
pound 4 with an isolated yield of 80% (Scheme 2).
Scheme 3. (A) Stepwise Photopolymerization of the Alloc-
TL Monomer 5 in a One-Pot Process Yielding a Linear
Polymer 6 with a Polythioether/Polyurethane Backbone and
Pendant Hydroxyl Groups; (B) 1H NMR Assignment (300
MHz) of the Alloc-TL Monomer 5 (top) and the Polymer 6
(bottom)
The structure of 4, which is a mixture of diastereoisomers, was
confirmed by NMR and MS analysis. An important conclusion
drawn from this model study is that the use of a photoinitiator
should be avoided or at least limited because of the interference
between the amine and radical fragments of the photoinitiator.
Radical thiol-ene conjugation can be performed in the absence of
a photoinitiator through irradiation with UV-light or sunlight.15
No further efforts were undertaken to modify the radical initia-
tion process as earlier reports showed that thermal initiators are
generally less efficient than photoinitiators for radical thiol-ene
conjugation14 and that H-abstraction type photoinitiators such as
benzophenone and thioxanthone react with amines with the for-
mation of the corresponding imines.16
Encouraged by the successful model study, we investigated the
synthesis of a monomer containing both a double bond and a
thiolactone unit. Similarly, Perrier et al.17 recently reported on
thiol-yne chemistry for the synthesis of hyperbranched struc-
tures using AB2 type (macro)monomers, molecules bearing a
thiol at one end of the molecule and an alkyne at the other. In our
case, as a thiolactone moiety can be considered as a precursor of a
thiol functionality, the combination with a double bond results in
an AB0 type monomer. The valorization of the reactivity of this
monomer, N-(allyloxy)carbonylhomocysteine thiolactone (Alloc-
TL) 5, upon aminolysis and subsequent UV-curing, would enable
us to develop convenient and accelerated protocols for the synthe-
sis of novel polymeric architectures. A scalable and high-yielding
synthesis of the proposed ene-thiolactone monomer consisted of
the treatment of homocysteine thiolactone with allyl chlorofor-
mate, introducing the corresponding (allyloxy)carbonyl or alloc
group, a popular amino-protecting group.
Radical (photo)polymerization reactions between a thiol and
an alkene occur in a stepwise fashion. Typically, a gradual in-
crease of the molecular weight with increasing conversion is
observed. In order to obtain high-molecular-weight poly addi-
tion compounds, the ratio between the involved functional
groups should equal 1. The aminolysis of the thiolactone in the
Alloc-TL monomer 5 to generate the thiol should therefore
efficiently reach full conversion. When using benzylamine in
the one-pot polyaddition reaction, polymer material could be
identified by size-exclusion chromatography (SEC), but even
after prolonged UV-curing, only low-molecular-weight material
(Mn < 5 kDa) was formed, compromising the purification via
precipitation and further analysis. On the other hand, in the
presence of a 2-fold excess of the nucleophile ethanolamine and
a small amount of DMPA (5 mol %), the polyaddition occurred
and, after 1 h of UV-curing, a white precipitate was obtained
(Scheme 3A). The purified polymer 6 was soluble in MeOH,
DMSO, DMF, and DMA and was analyzed by SEC and 1D and
2D NMR. The SEC chromatogram displayed a unimodal
distribution with a polydispersity index (PDI) of 1.6, and the
Mn, determined via SEC, was 22 kDa. The quantification of Mn
of the same polymer via end group analysis (double bond
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Scheme 4. Schematic Depiction of the Network Formation
(One-Pot Reaction between the Alloc-TL Monomer 5 and a
Diamine Cross-Linker 7 Results in a Polythioether Polyur-
ethane Network 8) and Structure of 4,9-Dioxadodecanedia-
mine 9 and Jeffamine D Series 10
reaction: the thiolactone ring opens upon aminolysis and the
in situ generated thiol reacts with a double bond, already present
in the same pot. A model study was elaborated to master the re-
action conditions. In order to valorize this reaction concept as an
accelerated protocol in polymer synthesis, an AB0 type monomer,
consisting of a double bond and a thiolactone moiety, was
synthesized and used to successfully assemble functional, linear
polymers and networks via a mild and facile radical photopo-
lymerization process. Future investigations will focus on the
development and valorization of the analogous amine-thiol-
yne reaction. Moreover, we are strongly convinced that this
methodology will be useful for the modification of double/triple
bond containing polymer materials.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures; syn-
b
thesis of model compounds; monomers and polymers; kinetic
studies; and NMR, LC-MS and IR data are included in the
Supporting Information. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
Filip.DuPrez@UGent.be
1
protons) in the H NMR spectrum (Scheme 3B) revealed a
molecular weight of 7.8 kDa.
’ ACKNOWLEDGMENT
This mild and efficient one-pot polyaddition process yielded a
polymer 6with a polythioether/polyurethane backbone and pendant
hydroxyl groups. We deliberately selected the ambident nucleophile
ethanolamine for the aminolysis: under neutral conditions, hydroxyl
functions are unable to open the thiolactone ring18 and alcohols do
not interfere with radical thiol-ene reactions.10 Standard synthetic
methods for the synthesis of hydroxyl functionalized polyurethanes
would certainly require a protection/deprotection strategy. Gen-
eralization of this reaction concept emphasizes the fact that, as long
as the additional functional group of the multifunctional amine
does not interfere with either reactions in the one-pot multistep
process (aminolysis and radical thiol-ene), linear polymers can be
obtained with direct introduction of side chain functional groups,
prone to post-polymerization modification.19
The authors are grateful for the financial support from the
Belgian Program on Interuniversity Attraction Poles initiated by
the Belgian State, Prime Minister’s office (Program P6/27).
’ REFERENCES
(1) Golas, P.; Matyjaszewski, K. Chem. Soc. Rev. 2010, 39, 1338–
1354. Sumerlin, B. S.; Vogt, A. P. Macromolecules 2009, 43, 1–13.
Hawker, C. J.; Wooley, K. L. Science 2005, 309, 1200–1205.
(2) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.;
Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew.
Chem., Int. Ed. 2004, 43, 3928–3932.
(3) Barner-Kowollik, C.; Inglis, A. J. Macromol. Chem. Phys. 2009,
210, 987–992.
(4) Lundberg, P.; Hawker, C. J.; Hult, A.; Malkoch, M. Macromol.
Rapid Commun. 2008, 29, 998–1015.
To further extend the scope of this methodology in material
science, polymer networks 8 based on the AB0 type monomer 5
were targeted. Anticipation of network formation was based
upon treatment of 5 with a diamine 7 under similar conditions as
described above (Scheme 4). Polymer film formation was expect-
ed upon UV-irradiation of a homogeneous reaction mixture be-
tween two glass plates, separated by a thin silicone spacer.
The choice of the diamine cross-linker 7 regarding structure
and molecular weight proved to be critical. 1,6-Hexanediamine
was insoluble in the reaction mixture. The use of the more polar
4,9-dioxadodecanediamine 9 as a cross-linker yielded a clear,
nontacky network film with good mechanical properties after
UV-curing for 3 h. The use of the Jeffamine D series 10 (D-400,
D-2000, and D-4000) as macromolecular cross-linkers was also
attempted, but poor film formation was observed, probably be-
cause the amine group is located on a secondary carbon atom,
thus sterically hampering cross-linking.
(5) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E.
Org. Lett. 2004, 6, 4223–4225. Beckmann, H. S. G.; Wittmann, V. Org.
Lett. 2007, 9, 1–4. Smith, N. M.; Greaves, M. J.; Jewell, R.; Perry,
M. W. D.; Stocks, M. J.; Stonehouse, J. P. Synlett 2009, 1391–1394.
(6) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004–2021.
(7) Becer, C. R.; Hoogenboom, R.; Schubert, U. S. Angew. Chem., Int.
Ed. 2009, 48, 4900–4908.
(8) Dondoni, A. Angew. Chem., Int. Ed. 2008, 47, 8995–8997. Kade,
M. J.; Burke, D. J.; Hawker, C. J. J. Polym. Sci., Part A: Polym. Chem. 2010,
48, 743–750. Lowe, A. B. Polym. Chem. 2010, 1, 17–36.
(9) Hoyle, C. E.; Lee, T. Y.; Roper, T. J. Polym. Sci., Part A: Polym.
Chem. 2004, 42, 5301–5338.
(10) Hoyle, C. E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49,
1540–1573.
(11) Xu, J.; Tao, L.; Boyer, C.; Lowe, A. B.; Davis, T. P. Macro-
molecules 2010, 43, 20–24.
(12) Chan, J. W.; Yu, B.; Hoyle, C. E.; Lowe, A. B. Chem. Commun.
2008, 4959–4961. Qiu, X. P.; Winnik, F. M. Macromol. Rapid Commun.
2006, 27, 1648–1653.
In conclusion, we have demonstrated that a thiolactone entity
can serve as a precursor for thiols in a one-pot amine-thiol-ene
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(13) Benesch, R.; Benesch, R. E. Proc. Natl. Acad. Sci. U.S.A. 1958,
44, 848–853.
(14) Uygun, M.; Tasdelen, M. A.; Yagci, Y. Macromol. Chem. Phys.
2010, 211, 103–110.
(15) Cramer, N. B.; Reddy, S. K.; Cole, M.; Hoyle, C.; Bowman,
C. N. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 5817–5826. ten
Brummelhuis, N.; Diehl, C.; Schlaad, H. Macromolecules 2008, 41, 9946–
9947.
(16) Texier-Boullet, F. Synthesis-Stuttgart 1985, 679–681.
(17) Konkolewicz, D.; Gray-Weale, A.; Perrier, S. J. Am. Chem. Soc.
2009, 131, 18075–18077.
(18) Aslam, M.; Dent, A. Bioconjugation: protein coupling techniques
for the biomedical sciences; Macmillan Reference Ltd.: 1998.
(19) Gauthier, M. A.; Gibson, M. I.; Klok, H. A. Angew. Chem., Int.
Ed. 2009, 48, 48–58.
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