A Modular approach to functionalized and expanded crown ether based macrocycles using click chemistry

Full text of DOI:10.1002/anie.200903156

Communications
DOI: 10.1002/anie.200903156
Macrocycles
A Modular Approach to Functionalized and Expanded Crown Ether
Based Macrocycles Using Click Chemistry**
Sandra Binauld, Craig J. Hawker, Etienne Fleury, and Eric Drockenmuller*
The synthesis and properties of macrocyclic structures is a
topic that has stimulated the interest of chemists for many
years. Indeed, macrocycles can be obtained from a variety of
reactions and find applications in a wide range of fields, such
novel macrocycles based on well-studied systems, such as
crown ethers. Similarly, several strategies have been used for
the step-wise construction of monodisperse oligomers, den-
dritic macromolecules, and linear or cyclic polymer chains.[9]
Uniting these two concepts, we present herein an efficient
strategy for the synthesis and characterization of a series of
molecularly defined ethylene glycol based oligomers and
their associated macrocycles that significantly enhances
structural diversity for these materials. By combining protec-
tion–deprotection and CuAAC exponential chain-growth
strategies, a-azide-w-alkyne-functionalized oligo(ethylene
glycol) derivatives were prepared (degree of polymerization
DP = 2n, with n = 0–3) and CuAAC intramolecular cycliza-
tion utilized to give a series of novel, molecularly defined
macrocycles with 1–8 triazole units in the cyclic backbone.
For a successful exponential growth strategy, the selection
of highly efficient coupling and protection–deprotection
reactions is crucial. Accordingly, the CuAAC process is an
ideal coupling reaction as it is quantitative, tolerant to a wide
range of reaction conditions; the azide and alkyne groups are
facile to introduce and to protect, respectively. Commercially
available 2-[2-(2-chloroethoxy)ethoxy]ethanol 1 was chosen
as an elementary tri(ethylene glycol) building block, as its
halogen and alcohol chain ends are readily converted into the
required azide and triisopropylsilyl-protected alkyne func-
tionalities by straightforward azidation and alkylation proce-
dures, respectively (Scheme 1). The diprotected unimer 3 was
synthesized by nucleophilic substitution of triisopropylsilyl
(TIPS) propargyl bromide 2 with the sodium salt of 1.[10]
Quantitative TIPS deprotection and azidation of 3 were
achieved using 5 equiv of tetrabutylammonium fluoride
as catalysis, metal extraction, and molecular recognition.[1]
A
continual synthetic challenge in macrocyclic chemistry is the
effectiveness of the strategies employed in their preparation.
Recently, the pioneering studies from Sharpless et al. and
Meldal et al. on copper(I)-catalyzed azide–alkyne cycloaddi-
tion (CuAAC) have paved the way for the development of
novel robust, efficient, and orthogonal synthetic
approaches.[2] This reaction, often assimilated to the click
chemistry philosophy, has been widely applied to the versatile
and efficient synthesis or functionalization of a broad range of
molecules, surfaces, and macromolecular architectures.[3]
The supported synthesis of macrocycles by CuAAC
intramolecular cyclization of azide–alkyne difunctional
amino acids was first reported by Meldal et al.[4] Since then,
the CuAAC synthesis of macrocycles has been primarily
applied to peptidic and carbohydrate structures, with mono-
cycle yields ranging from 20 to 95% depending on the length,
conformation, and sequence of the linear precursors, and on
the experimental conditions.[5] High-dilution conditions (ca.
1–2 mm) are usually necessary to decrease the occurrence of
step-growth polymerization in favor of the formation of
macrocyclic monoadducts,[6] whilst for select systems, the
formation of macrocyclic dimers by head-to-tail cyclodime-
rization predominates.[7] More recently, CuAAC intramolec-
ular cyclizations have also been performed on tailor-made
a-azide-w-alkyne linear macromolecular precursors under
pseudo-high-dilution conditions using a continuous addition
system, leading to a range of novel macrocyclic polymers.[8]
This increased efficiency in macrocyclization afforded by
CuAAC chemistry, and especially for ultralarge rings, there-
fore opens up significant opportunities to prepare a range of
[*] S. Binauld, Prof. E. Fleury, Dr. E. Drockenmuller
Universitꢀ Claude Bernard Lyon 1, INSA Lyon
Ingꢀnierie des Matꢀriaux Polymꢁres, UMRCNRS 5223
69622 Villeurbanne (France)
Fax: (+33)4-7889-2583
E-mail: eric.drockenmuller@univ-lyon1.fr
Prof. C. J. Hawker
Departments of Materials, University of California
Santa Barbara, CA 93106–9510 (USA)
[**] The authors are grateful to Dr. E. Jeanneau from the Centre de
Diffractomꢀtrie Henri Longchambon, Universitꢀ Claude Bernard
Lyon 1, for the single X-ray data collection, structure solutions, and
refinements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903156.
Scheme 1. Synthesis of a,w-diprotected unimer 3, monoprotected
w-alkyne unimer 4 and a-azide unimer 5.
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(TBAF) to give 4, or 3 equiv of sodium azide in DMF to give
5. As previously mentioned,[11] triisopropylsilyl (TIPS) was
preferred to trimethylsilyl (TMS), as partial removal of the
TMS group was observed during reaction with sodium azide.
CuAAC coupling of 4 and 5 in chloroform at 608C using
[CuIP(OEt)3] and diisopropylethylamine (DIPEA) as the
catalytic system yielded the desired a-chloro-w-TIPS-dipro-
tected dimer 6 in almost quantitative yields (Scheme 2). To
ensure the absence of contamination from lower oligomer
starting materials in the final product, a slight excess
(1.05 equiv) of alkyne 4 was employed in the coupling
reaction, and this excess was removed using a novel poly-
mer-based scavenging technique based on the method of
Monteiro et al. for the purification of alkyne- or azide-
functionalized polymers using resins bearing the correspond-
ing azide or alkyne groups.[12] In the previous work, the
separation of dendritic polymers from functionalized linear
precursors of the same chemical nature requires the use of
crosslinked resins. For the separation of a,w-diprotected
dimer 6 from the excess alkyne unimer 4, a non-crosslinked
polymer substrate bearing azide groups could be used, and the
soluble nature of the scavenger increases the efficiency of the
process. Therefore, poly(styrene-co-4-azidomethyl styrene)
(Mn ꢀ 150 kDa, 10 mol% of azidomethyl units, 2 equiv of
azides according to the excess of alkyne groups) was added to
the reaction media and stirred for four additional hours to
promote the CuAAC grafting of the excess of alkyne
derivative 4 to the random copolymer backbone.[13] After
the scavenging reaction, pure a-chloro-w-TIPS-diprotected
Scheme 2. Synthesis by CuAAC coupling of a-w-protected dimer 6, and
purification of excess w-alkyne unimer 4 using a poly(styrene-co(4-
azidomethyl styrene)) soluble scavenger. DIPEA=diisopropylethyl-
amine.
blocks and a DP of 8, the power of this strategy can be
appreciated by facile extension to higher-generation hetero-
dimer
6 could be easily
recovered by precipitation
of the grafted random copo-
lymer in methanol. The effi-
ciency of this purification
procedure was confirmed by
1H NMR and 13C NMR spec-
troscopy,
mass
(HRMS),
high-resolution
spectrometry
size-exclusion
chromatography (SEC), and
FTIR spectroscopy, with all
methods confirming the high
purity of 6 and the absence
of unreacted starting materi-
als.
This high level of syn-
thetic ease and efficiency
allows
chain-growth strategy to be
facile process yielding
the
exponential
a
higher-generation function-
alized oligomers up to the
octamer (Scheme 3); that is,
a-chloro-w-alkyne (7 and
10), a-azide-w-TIPS (8, 11,
and 13), and a-chloro-w-
TIPS (9 and 12). Although
limited in this case to tri(-
Scheme 3. Iterative strategy for the synthesis of molecularly defined mono- and di-protected tri(ethylene
glycol)-based oligomers (n=2, 4, and 8): a) TBAF, THF, 15 h, RT; b) NaN3, DMF, 24 h, 708C; c) [CuIP(OEt)3],
DIPEA, CHCl3, 4 h, 608C; d) Addition of poly(styrene-co-(4-azidomethyl styrene)), further reaction for 4 h at
ethylene glycol) building 608C and purification by precipitation in MeOH.
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functionalized oligomers eventually prepared from a wide
variety of other building blocks.
much higher concentration of catalyst to ensure a fast
CuAAC intramolecular reaction.
The last step before cyclization was TBAF deprotection of
a-azide-w-TIPS derivatives 5, 8, 11, and 13 to give a-azide-w-
alkyne reactive oligomers 14–17 with DP = 2n and n = 0–3
(Scheme 4). This pathway was preferred to the azidation of
Initially, a solution of a-azide-w-alkyne unimer 14 in H2O
was added dropwise (0.15 mLminÀ1) to
a solution of
CuSO4·5H2O and sodium ascorbate in water maintained at
608C, and after complete addition macrocycle 18 was purified
by recrystallisation from diethyl ether. 1H and 13C NMR of the
resulting macrocycle revealed the appearance of a new
triazole proton signal at d = 7.98 ppm and an associated
shift of the signals corresponding to the methylene groups
adjacent to the triazole ring at d = 4.69 and 4.47 ppm. The
disappearance of the signals corresponding to the CH2N3 and
ꢁ
CH2C CH chain ends further confirmed the quantitative
intramolecular cyclization reaction. Furthermore, the com-
plex splitting patterns for the resonances corresponding to the
À
À
OCH2CH2O moieties compared to the signals for the
corresponding linear derivative was diagnostic for a more
constrained, cyclic system. Finally, the lack of discernable
differences between the linear and cyclic species in the
HRMS spectra verifies the absence of coupled, higher-
molecular-weight derivatives.
The CuAAC cyclization reaction was found to be a facile
process for all a-azide-w-alkyne oligomers 14–17 that were
studied, with yields of 85–90% in each case at concentrations
significantly greater than for traditional click-based
approaches. SEC, HRMS, and 1H and 13C NMR spectroscopy
confirmed the formation of the targeted macrocycles 18–21
with ring sizes ranging from 14 to 56 atoms and the number of
triazole units contained within the macrocycle ranging from 1
to 8. Therefore, this strategy allows the efficient synthesis of
novel crown-ether based macrocycles containing aromatic,
electron-rich triazole rings that are capable of supramolecular
interactions.
The efficiency of this strategy can be seen in Figure 1: the
SEC traces are narrow and monomodal in all cases. More-
over, these results highlight the dramatic effect that macro-
cyclization has on molecular size, showing a decrease in
hydrodynamic volume after cyclization that is fully consistent
with the formation of cyclic species. Mass spectrometry
analyses of a-azide-w-alkyne precursors and the correspond-
ing macrocycles matched the anticipated molecular formulas
very well (Table 1). The physical properties of the macro-
cycles were also significantly different compared to their
corresponding noncrystalline linear analogues; for example,
the macrocycles 18 and 19 are highly crystalline (Table 1).
Comparison of the melting temperatures obtained from DSC
with those for the well-known crown ethers, such as
[12]crown-4 and [18]crown-6 (Tm = 168C and 408C, respec-
tively), also showed a significant enhancement, presumably
owing to the contribution of the highly polar and hydrogen
bonding triazole unit(s).
Scheme 4. Synthesis of molecularly defined a-azide-w-alkyne reactive
oligomers 14–17 and corresponding macrocycles 18–21. NaAsc=
sodium ascorbate.
a-chloro-w-TIPS derivatives to avoid any thermal CuAAC
step-growth polymerization prior to the cyclization step. The
resulting a-azide-w-alkyne oligomers 14–17 were stored at
À208C, and were found to be stable for several months at this
temperature. The efficiency and the orthogonal character of
each step of this iterative step growth strategy was verified
using 1H and 13C NMR spectroscopy by monitoring the
chemical shifts of the groups adjacent to the chain ends and
triazole groups. Furthermore, SEC and HRMS character-
ization of each intermediate confirmed the absence of lower
and higher generation byproducts and showed single molec-
ular ions corresponding to the desired functionalized oligom-
ers.
The fundamental synthetic challenge, that is, the optimi-
zation of macrocyclic formation from the molecularly defined
a-azide-w-alkyne oligomers 14–17, was then examined using a
pseudo-high-dilution strategy. Previous studies regarding the
effect of monomer dilution during the CuAAC step-growth
polymerization of a-azide-w-alkyne monomers have shown
that yields of monocyclization as high as 60% could be
attained using monomer concentrations of about 1 mm.[14] To
improve the yield and efficiency of macrocycle formation,
cyclization experiments were performed using a peristaltic
pump for the controlled addition of monomer solutions to a
solution of the catalytic system maintained at 608C. In this
way, the reaction mixture contains a relatively dilute solution
of the monomer at all times, and the monomer is exposed to a
Table 1: Molar mass and thermal properties of macrocycles 18–21.
No. Theor. Mw (gmolÀ1
)
m/z [gmolÀ1
]
Tm [8C] DHm [JgÀ1
]
18
19
20
21
213.2
426.5
852.9
214.0 [M+H+]
449.2 [M+Na+]
875.3 [M+Na+]
1727.4 [M+Na+]
90
118
–
52
59
–
1705.8
–
–
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CuAAC couplings, azidation, and TIPS-deprotection modifi-
cation of the chain ends. Subsequent CuAAC intramolecular
cyclization, performed under pseudo-high-dilution condi-
tions, was shown to be a facile, high-yielding process, giving
a series of novel macrocycles in which the ring size and
number of electron-rich triazole units in the macrocycle can
be accurately controlled. The correlation between ring size,
number of triazole units, and binding properties toward
organic or metallic cations is currently under investigation.
Experimental Section
Characterization and methods for all compounds can be found in the
Supporting Information. CCDC 735276 and CCDC 735277 contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Single-crystal X-ray diffraction data for 18: C9H15N3O3, Mr =
213.24, 0.49 ꢀ 0.15 ꢀ 0.1 mm3, monoclinic (P21/c), a = 9.5901(7), b =
13.4823(7), c = 9.3915(8) ꢁ, b = 118.249(11)8, V= 1069.67(17) ꢁ3,
Z = 4, m = 0.10 mmÀ1, T= 293 K, 2665 measured reflections, 1559
independent (R(int) = 0.046),
R
(F2 > 2s(F2)) = 0.059, wR(F2) =
0.052, D1 (min,max) = À0.17, 0.15 eꢁ3. 19: C18H30N6O6, Mr =
426.47, 0.12 ꢀ 0.06 ꢀ 0.05 mm3, monoclinic (C2/c), a = 25.507(10), b =
4.4464(11), c = 18.584(4) ꢁ, b = 101.60(3)8, V= 2064.6(10) ꢁ3, Z = 4,
m = 0.87 mmÀ1, T= 150 K, 8821 measured reflections, 2588 independ-
ent (R(int) = 0.046),
R
(F2 > 2s(F2)) = 0.091, wR(F2) = 0.250, D1
(min,max) = À0.65, 0.57 eꢁ3.
Received: June 11, 2009
Published online: August 4, 2009
Figure 1. Size-exclusion chromatography traces of molecularly-defined
a-azide-w-alkyne oligomers 14–17 and corresponding macrocycles
18–21.
Keywords: click chemistry · copper · cyclization ·
.
iterative strategies · macrocycles
Examination of single crystals of the macrocycles 18 and
19 by X-ray diffraction experiments (Figure 2) confirmed
their rigid and strained cyclic conformation. In comparison
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