COMMUNICATION

pubs.acs.org/JACS

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
bS Supporting Information
based on metal-free radical thiol-ene chemistry in order to modify
ABSTRACT: The in situ generation of thiols by nucleo- or assemble polymeric materials. In addition to the fact that the
philic ring-opening of a thiolactone with amines, followed by commercial availability of thiols as starting materials is rather limited,
a UV-initiated radical thiol-ene reaction in a one-pot fashion, thiols usually have an unpleasant smell and might have a poor shelf
has been evaluated as an accelerated and versatile protocol life due to oxidation reactions. Therefore it can be advantageous to
for the synthesis of several types of polymeric architectures. generate thiols in situ and convert them in a one-pot process. In a
After elaboration of a model amine-thiol-ene conjuga- very recent report on a metal-free two-step approach,11 a dithio-
tion reaction, a number of routes based on readily available benzoate at the ω chain end of a polymer obtained via RAFT
thiolactone-containing structures have been developed to (reversible addition-fragmentation chain transfer) was converted
successfully assemble functional, linear polymers and networks to the corresponding thiol via aminolysis and this thiol acted as a
via a mild and facile radical photopolymerization process. 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
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-
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
box of synthetic macro- and supramolecular research groups.1
ε-NH2 groups of lysine residues. We anticipated the ability to
One of the major virtues of the ‘click’ concept has been, since its
adapt this methodology and combine it with the radical thiol-
introduction in polymer science,2 the paradigm shift toward a
ene process in a one-pot fashion as a mild approach for the synthesis
modular construction approach of complex innovative polymeric
of polymeric architectures starting from stable amine containing
architectures.3 In addition to this awareness, the challenge was
compounds. Although the presented concept (Scheme 1) might
taken up to combine these robust, efficient, and orthogonal con-
not be broadly applicable due to the reactive nature of amines and
jugation chemistries, resulting in the development of several ele-
radical species (orthogonality issues), this amine-thiol-ene con-
gant one-pot, multistep strategies, enabling the implementation
jugation as a simple, efficient, and modular linking process is con-
of accelerated synthetic protocols.4 An important class of one-
sidered to be a relevant extension of the currently quite popular
pot, multistep reactions is characterized by the fact that all
thiol-ene chemistry, especially in polymer science.
chemicals initially are mixed and consecutive reactions depend
In the first stage of this study, the one-pot two-step sequence
on each other. For example, a potentially explosive azide can be
was performed on low-molecular-weight model compounds in
generated in situ, starting from the corresponding bromide via
order to investigate the reaction kinetics and to analyze the com-
nucleophilic substitution or amine via diazotransfer, and can
position of the obtained reaction mixture. Benzylamine 2 was
subsequently be converted to a triazole via the copper-catalyzed
treated with thiolactone 1 in the presence of 4-dimethylamino-
azide-alkyne cycloaddition (CuAAC) in the same pot.5 So far,
pyridine (DMAP) as a nucleophilic catalyst. In the initial reaction
virtually all of these one-pot reaction sequences encompass the
mixture, an excess of norbornene (ene-compound) 3 was added
heavily exploited Huisgen CuAAC as the key step. The main
to allow for the subsequent radical thiol-ene reaction. The reac-
disadvantage of this popular ‘click’ reaction, ruling out many
tion mixture was irradiated by an external UV-light source, and
potential applications, is the presence of complexed copper in the
2,2-dimethoxy-2-phenyl acetophenone (DMPA) was selected as
reaction products. Currently, metal-free methodologies which
an efficient photoinitiator for thiol-ene conjugation.14 Because
fulfill the set of ‘click’ requirements6 are eagerly developed and
of the extremely high reactivity of the norbornene double bond
evaluated.7 The radical or nucleophilic addition of a thiol to a
toward thiyl radicals,9 the first step of the reaction sequence was
double bond (thiol-ene chemistry8-10) has recently been re-
considered to be rate-determining. In an online 1H NMR experi-
cognized as a valuable metal-free alternative for the CuAAC due
ment, the consumption of 2 was monitored by the decrease of the
to some inherent ‘click’ characteristics.
signal of the corresponding benzylic protons. This study pointed
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, Received: November 1, 2010
our ongoing interest is to develop an efficient one-pot process Published: January 25, 2011

r 2011 American Chemical Society 1678 dx.doi.org/10.1021/ja1098098 | J. Am. Chem. Soc. 2011, 133, 1678–1681
Journal of the American Chemical Society COMMUNICATION

Scheme 1. General Concept of the Investigated Metal-Free Scheme 2. Model Amine-Thiol-Ene Conjugation: One-
One-Pot Reaction: Nucleophilic Opening of a Thiolactone Pot Reaction between Benzylamine, N-Acetylhomocysteine
(Aminolysis), Followed by a Radical Thiol-Ene Conjugation 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 Scheme 3. (A) Stepwise Photopolymerization of the Alloc-
after the two-step reaction by LC-MS revealed, in addition to the TL Monomer 5 in a One-Pot Process Yielding a Linear
presence of the desired compound 4, the formation of side prod- Polymer 6 with a Polythioether/Polyurethane Backbone and
ucts, originating from the reaction between 2 and radical frag- Pendant Hydroxyl Groups; (B) 1H NMR Assignment (300
ments of DMPA (Figure S2). However, using optimal conditions MHz) of the Alloc-TL Monomer 5 (top) and the Polymer 6
(no photoinitiator) and after a straightforward chromatographic (bottom)
purification, the model reaction yielded the conjugation com-
pound 4 with an isolated yield of 80% (Scheme 2).
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 after prolonged UV-curing, only low-molecular-weight material
group, a popular amino-protecting group. (Mn < 5 kDa) was formed, compromising the purification via
Radical (photo)polymerization reactions between a thiol and precipitation and further analysis. On the other hand, in the
an alkene occur in a stepwise fashion. Typically, a gradual in- presence of a 2-fold excess of the nucleophile ethanolamine and
crease of the molecular weight with increasing conversion is a small amount of DMPA (5 mol %), the polyaddition occurred
observed. In order to obtain high-molecular-weight poly addi- and, after 1 h of UV-curing, a white precipitate was obtained
tion compounds, the ratio between the involved functional (Scheme 3A). The purified polymer 6 was soluble in MeOH,
groups should equal 1. The aminolysis of the thiolactone in the DMSO, DMF, and DMA and was analyzed by SEC and 1D and
Alloc-TL monomer 5 to generate the thiol should therefore 2D NMR. The SEC chromatogram displayed a unimodal
efficiently reach full conversion. When using benzylamine in distribution with a polydispersity index (PDI) of 1.6, and the
the one-pot polyaddition reaction, polymer material could be Mn, determined via SEC, was 22 kDa. The quantification of Mn
identified by size-exclusion chromatography (SEC), but even of the same polymer via end group analysis (double bond
1679 dx.doi.org/10.1021/ja1098098 |J. Am. Chem. Soc. 2011, 133, 1678–1681
Journal of the American Chemical Society COMMUNICATION

Scheme 4. Schematic Depiction of the Network Formation reaction: the thiolactone ring opens upon aminolysis and the
(One-Pot Reaction between the Alloc-TL Monomer 5 and a in situ generated thiol reacts with a double bond, already present
Diamine Cross-Linker 7 Results in a Polythioether Polyur- in the same pot. A model study was elaborated to master the re-
ethane Network 8) and Structure of 4,9-Dioxadodecanedia- action conditions. In order to valorize this reaction concept as an
mine 9 and Jeffamine D Series 10 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

bS Supporting Information. Experimental procedures; syn-

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
[email protected]
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 The authors are grateful for the financial support from the
polymer 6 with a polythioether/polyurethane backbone and pendant Belgian Program on Interuniversity Attraction Poles initiated by
hydroxyl groups. We deliberately selected the ambident nucleophile the Belgian State, Prime Minister’s office (Program P6/27).
ethanolamine for the aminolysis: under neutral conditions, hydroxyl
functions are unable to open the thiolactone ring18 and alcohols do ’ REFERENCES
not interfere with radical thiol-ene reactions.10 Standard synthetic
methods for the synthesis of hydroxyl functionalized polyurethanes (1) Golas, P.; Matyjaszewski, K. Chem. Soc. Rev. 2010, 39, 1338–
1354. Sumerlin, B. S.; Vogt, A. P. Macromolecules 2009, 43, 1–13.
would certainly require a protection/deprotection strategy. Gen- Hawker, C. J.; Wooley, K. L. Science 2005, 309, 1200–1205.
eralization of this reaction concept emphasizes the fact that, as long (2) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.;
as the additional functional group of the multifunctional amine Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew.
does not interfere with either reactions in the one-pot multistep Chem., Int. Ed. 2004, 43, 3928–3932.
process (aminolysis and radical thiol-ene), linear polymers can be (3) Barner-Kowollik, C.; Inglis, A. J. Macromol. Chem. Phys. 2009,
obtained with direct introduction of side chain functional groups, 210, 987–992.
prone to post-polymerization modification.19 (4) Lundberg, P.; Hawker, C. J.; Hult, A.; Malkoch, M. Macromol.
To further extend the scope of this methodology in material Rapid Commun. 2008, 29, 998–1015.
science, polymer networks 8 based on the AB0 type monomer 5 (5) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E.
were targeted. Anticipation of network formation was based 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,
upon treatment of 5 with a diamine 7 under similar conditions as M. W. D.; Stocks, M. J.; Stonehouse, J. P. Synlett 2009, 1391–1394.
described above (Scheme 4). Polymer film formation was expect- (6) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
ed upon UV-irradiation of a homogeneous reaction mixture be- 2001, 40, 2004–2021.
tween two glass plates, separated by a thin silicone spacer. (7) Becer, C. R.; Hoogenboom, R.; Schubert, U. S. Angew. Chem., Int.
The choice of the diamine cross-linker 7 regarding structure Ed. 2009, 48, 4900–4908.
and molecular weight proved to be critical. 1,6-Hexanediamine (8) Dondoni, A. Angew. Chem., Int. Ed. 2008, 47, 8995–8997. Kade,
was insoluble in the reaction mixture. The use of the more polar M. J.; Burke, D. J.; Hawker, C. J. J. Polym. Sci., Part A: Polym. Chem. 2010,
4,9-dioxadodecanediamine 9 as a cross-linker yielded a clear, 48, 743–750. Lowe, A. B. Polym. Chem. 2010, 1, 17–36.
nontacky network film with good mechanical properties after (9) Hoyle, C. E.; Lee, T. Y.; Roper, T. J. Polym. Sci., Part A: Polym.
UV-curing for 3 h. The use of the Jeffamine D series 10 (D-400, Chem. 2004, 42, 5301–5338.
(10) Hoyle, C. E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49,
D-2000, and D-4000) as macromolecular cross-linkers was also 1540–1573.
attempted, but poor film formation was observed, probably be- (11) Xu, J.; Tao, L.; Boyer, C.; Lowe, A. B.; Davis, T. P. Macro-
cause the amine group is located on a secondary carbon atom, molecules 2010, 43, 20–24.
thus sterically hampering cross-linking. (12) Chan, J. W.; Yu, B.; Hoyle, C. E.; Lowe, A. B. Chem. Commun.
In conclusion, we have demonstrated that a thiolactone entity 2008, 4959–4961. Qiu, X. P.; Winnik, F. M. Macromol. Rapid Commun.
can serve as a precursor for thiols in a one-pot amine-thiol-ene 2006, 27, 1648–1653.

1680 dx.doi.org/10.1021/ja1098098 |J. Am. Chem. Soc. 2011, 133, 1678–1681

Journal of the American Chemical Society COMMUNICATION

(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.

1681 dx.doi.org/10.1021/ja1098098 |J. Am. Chem. Soc. 2011, 133, 1678–1681