Highly efficient divergent synthesis of dendrimers via metal-free click chemistry

Article abstract of DOI:10.1002/pola.26511

A new synthetic strategy to prepare dendrimers using a single, inexpensive monomer is described. Divergent growth relies on a highly efficient, metal-free Click cycloaddition of azides to alkynes. Functional dendrimers are obtained with minimal purification in high yields, with no by-product but a water soluble salt, and the excess of monomer used can be recycled at each stage of the iterative synthesis.

Full text of DOI:10.1002/pola.26511

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Highly Efficient Divergent Synthesis of Dendrimers via
Metal-Free ‘‘Click’’ Chemistry
Ferdinand Gonzaga, Lukas P. Sadowski, Talena Rambarran, John Grande,
Alex Adronov, Michael A. Brook
Department of Chemistry and Chemical Biology, McMaster University, West Hamilton, Ontario L8S4M1, Canada
Correspondence to: F. Gonzaga (E-mail: ferdinandgonzaga@hotmail.com)
Received 19 September 2012; accepted 15 November 2012; published online 26 December 2012
DOI: 10.1002/pola.26511
KEYWORDS: alkynes; azides; click chemistry; dendrimers; metal-free; monomers; synthesis
Since the pioneering work of Flory in the early 50s,1 the con-
struction of well-defined, hyperbranched macromolecular
structures have undergone remarkable development.2 In par-
ticular, a multitude of creative approaches to the synthesis of
chemistry’’) would be highly valuable in biological applica-
tions. Metal-free click alternatives were recently developed,
and this growing field of research was recently reviewed:17
in particular, electron-deficient, that is activated alkynes,
such as acetylene dicarboxylate derivatives, were found to
click with azides at low temperatures, without the need of a
copper catalyst.18 Even alkynes activated by a unique carbox-
ylic acid or ester functionality, such as esters of propiolic
acid, are able to react with azides at room temperature.19
When such electronic effects are combined with ring strain
activation (Strain Promoted Alkyne Azide Cycloaddition or
SPAAC), the methodology becomes even more powerful,
allowing the modification of living systems20 or the in vivo
imaging of embryos,21 as demonstrated by the elegant work
of Bertozzi and coworkers. Surprisingly, synthetic strategies
using metal-free, azide to alkyne cycloadditions are
extremely rare in the literature, with the exception of a sin-
dendrimers have been reported: from the original divergent
3
€
approach introduced by Vogtle and coworkers, Newkome
et al.,4 and Tomalia et al.,5 followed by the convergent
approach from Hawker and Frechet, the development of ef-
6
ꢀ
ficient synthetic routes to dendrimers opened an entirely
new field of research and of potential applications.7 How-
ever, most of the original divergent approaches suffered from
several drawbacks, such as incomplete reactions (leading to
structural defects) or were tedious and time-consuming due
to protection-deprotection steps and/or chromatographic pu-
rification, limiting their practicality.8 In the last decade, the
introduction of highly-efficient, by-product free chemical
transformations, known as Click chemistry,9 have further
pushed back these limits in the assembly of dendrimers.10
A
ꢀ
gle report where Frechet-type dendrons bearing an activated
alkyne were clicked onto a polyazido core;22 however, the
method described there still relies on classical ether-type
chemistry, and does not fulfill the requirements of click
chemistry. Ideally, from an application point of view, a practi-
cal dendrimer synthesis should: be high-yielding, rely on a
single and simple precursor, not involve any metal, and
would not require solvents, heat (or as little as possible) or
chromatographic purifications.
major breakthrough was the introduction of copper(I)-cata-
lyzed cycloadditions of alkynes to azide (CuAAC) by Sharp-
less,11 followed by the impressive work of Hawker on the
thiolene based synthesis of dendrimers,8,12 and the elegant
combination of multiple, orthogonal Click reactions.13 Both
divergent14 and convergent11 strategies were found to bene-
fit from the efficiency of the CuAAC methodology. However,
the use of copper catalyst is a potential drawback for bio-
medical applications (due to its cytotoxicity), in particular in
large molecules containing multiple functional groups able to
bind copper ions.15 Recently, it was shown that functionaliza-
tion of poly(amido)-based dendritic molecules with poly(eth-
ylene glycol) chains using CuAAC resulted in dendrons conta-
minated by significant amounts of copper, ruling out their
use in pharmaceutical applications.16 Therefore, strategies
combining the practical use and advantages of the CuAAC
without the need of a metal catalyst (‘‘metal-free click
Here, we report such a strategy, based on the metal-free
cycloaddition of alkynes to azides: high-generation den-
drimers are obtained with minimal purification in high
yields, with no byproducts but a water soluble salt, and the
excess of monomer used can be recycled at each stage of the
iterative synthesis. The same strategy also allows versatile
surface functionalization, from bromo-alkyl moieties (one of
the most versatile functionality in organic chemistry) to
Additional Supporting Information may be found in the online version of this article.
C
V
2012 Wiley Periodicals, Inc.
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(metal-free click reaction) to yield the corresponding triazole
derivatives. The 2-bromopropyl moieties would lead to quan-
titative formation of the desired diazidopropyl groups, which
could then be coupled with BBBD to give the next generation
bromo-terminated dendrimer.
SCHEME 1 Synthesis of bis(bromopropyl) but-2-yne dioate
(BBBD) 1. (a) Benzene, pTSA (catalytic), Dean-Stark, 26 h.
To test the validity of the approach, we performed the syn-
thesis of the first generation bromo-terminated dendrimer,
as illustrated in Scheme 2. Metal-free click chemistry
between BBBD 1 and 1,4-bis azidomethyl benzene was per-
formed by simply mixing the reagents in a scintillation vial,
at room temperature and without any catalyst. A small
excess of alkyne was used (1.5 equivalent per azido group),
and 1 mL of deuterated chloroform was added. Although sol-
vent was not strictly required to perform the reaction, the
small amount of deuterated chloroform prevented gelation of
the reaction medium (bromo-terminated dendrimer 2a is a
solid and precipitated in the vial, preventing stirring), and
allowed easy monitoring of the reaction by 1H NMR. The
dendrimer core was chosen due to the fact that it is readily
prepared from commercially available precursors, but also
water-soluble polycarboxylates, opening access to a wide
range of potential applications.
Our work started with the design of an alkyne monomer
that could, in a first step, easily click on a poly(azide) core,
and subsequently, upon selective activation, allows further
growth of the dendrimer following a divergent process. The
selected monomer, bis(bromopropyl) but-2-yne dioate (or
BBBD, 1) was easily prepared from commercially available
precursors, as depicted in Scheme 1.
Conventional Fischer esterification of but-2-yne dioic acid
(acetylene dicarboxylic acid) with 2-bromopropanol in ben-
zene yielded 1 in a 96% yield after chromatography (see Ex-
perimental sections for detailed procedures). The internal,
activated alkyne functionality should allow metal-free Click
ligation to azido derivatives: indeed, we19 and others23 have
shown that esters of propiolic- or acetylene dicarboxylic-
acids undergo facile, uncatalyzed thermal (or even room
temperature) Huisgen 1,3-dipolar cycloaddition to azides
1
because of its H NMR characteristics.
The four equivalent aromatic protons appear as a singlet at
7.35 ppm, while the benzilic methylene groups (also a sin-
glet) appear at 4.36 ppm. Upon clicking, these methylene
protons shifted from 4.36 ppm in the azido derivative to
5.79 ppm in the first generation dendrimer 2a. Thus, both
SCHEME 2 Synthesis of bromo-terminated or azido-terminated dendrimers via metal-free click chemistry.
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FIGURE 1 1H NMR spectra of G1-Br (trace a), G1-N3 (trace b), G2-Br (trace c), and G3-Br (trace d). All spectras were calibrated on
the four methylene protons in position a of the first generation triazole rings. Signals marked with a star correspond to residual
DCM (5.29 ppm) and acetone (2.17 ppm).
signals can be used to calibrate integrations in proton NMR
and allow easy monitoring of the reaction: completion of the
reaction was achieved in 6 h, and the first generation
bromo-terminated dendrimer 2a or G2-Br was obtained in a
99% isolated yield after a simple filtration over a short pad
of silica (in the following text, the nomenclature G will refer
to the generation number, while the added ‘‘-Br’’ or ‘‘N3’’
refers to the surface functionality: for example, G3-Br indi-
cates a 3rd generation dendrimer, bromo-terminated). More
importantly, that simple procedure allowed recovery of the
excess alkyne (95% of the theoretical amount was recov-
ered), for further use in the building of higher generation
dendrimers. From 2a, easy nucleophilic displacement of the
bromo by the azide anion in DMSO afforded the correspond-
ing tetra(azido)-terminated first generation dendrimer 2b
(96%; see Experimental section for detailed procedures),
using a simple aqueous workup. Proton and carbon NMR
experiments proved without any ambiguity the complete
conversion of the 4 bromopropyl chains into the correspond-
ing azidopropyl moieties, as well as high-resolution mass
spectroscopy. The evolution in the NMR signals from G1-Br
to G1-N3 are shown in Figure 1: multiplicities and integra-
tions are unchanged, while chemical shifts are moved to
lower frequencies for each type of proton (in particular, the
2 signals corresponding to the 4 methylene protons in posi-
tion b to the bromo atoms are lowered from 2.31 and 2.18
ppm to 2.03 and 1.91 ppm, respectively). The successful syn-
thesis of azido-terminated dendrimer in an overall 95% iso-
lated yield proved the efficiency of these two synthetic steps:
successive metal-free ligation and azidation should allow a
successful divergent synthesis of higher generation
dendrimers.
This hypothesis was tested with the construction of den-
drimers of 2nd, 3rd, and even 4th generation, using the
same iterative synthetic steps. Generation 2, bromo-termi-
nated 3a was obtained in 97% yield, along with 94% of the
excess recovered monomer 1. Proton NMR confirmed com-
pletion of the reaction and the obtention of pure G2 den-
drimer, as shown in Figure 1 (traces b and c for G1-N3 and
G2-Br, respectively): the 2 inequivalent sets of triplets, at
3.38 and 3.47 ppm, corresponding to the 8 protons in alpha
of the azido groups, are now replaced by a single triplet res-
onance at 3.53 ppm, corresponding to the 16 protons alpha
to the external bromo moieties. The 2 singlets at 5.78 and
7.26 ppm, corresponding to the benzylic methylene and the
aromatic ring protons, respectively, are now shifted to 5.81
and 7.30 ppm, along with the appearance of 8 new protons
corresponding to the methylene group alpha to the new 4
triazole rings. HR-MS confirmed a molecular weight of
2172.9g molꢀ1. Compound 3a was readily converted into the
azido-terminated, 2nd generation dendrimer 3b (95% yield)
using the same azidation procedure in DMSO. Interestingly,
while the methylenic protons alpha to the external bromo
groups in 3a appear as a single triplet (despite their chemi-
cal environment non-equivalence), they now appear as a
multiplet (which seems to be overlapping triplet signals) in
3b; however, carbon NMR showed a single resonance at
53.53 ppm for the 8 carbons in position a to the surface
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azido moieties. HR-MS also confirmed the expected molecu-
lar weight of 1868.8 g molꢀ1. Click ligation of 1 to 3b
yielded generation 3 dendrimer, bromo-terminated 4a in 48
h at room temperature (96% yield; 4717.69 g molꢀ1 molecu-
lar weight). Proton NMR, as shown in Figure 1 (trace d),
confirmed completion of the reaction: the total number of
protons in position a of the bromo moieties is now 32 (and
appears now as a multiplet, which also indicates reduced
end-chain mobility as the generation number increases) and
clearly shows the total number of methylene protons in posi-
tion a to the triazoles now to be 24, as well as the 56 meth-
ylene protons in position a to the carboxylate esters. It is
interesting to point out that, using a 600 MHz NMR
spectrometer, proton NMR allows one to precisely monitor
completion of the click reactions as well as the synthesis of
dendrimers that appear defect-free: variations between the
theoretical number of protons in the structure and the ex-
perimental integrations observed in the NMR spectra of G3-
Br dendrimer ranged between 0.79% and 1.53% only,
depending on the signal chosen. The purification of 4a can
be accomplished similarly to the previous generations (short
filtration over silica gel), but we also found that precipitation
of the crude reaction mixture in dry-ice cold diethyl ether
afforded the pure dendrimer as a solid that can be easily
filtered, while the excess monomer was recovered in the fil-
trate (a double precipitation procedure was followed to
ensure purity of the dendrimer). Isolated purified 4a can
then easily be converted into the corresponding azide-termi-
nated dendrimer 4b in a 95% yield (see Supporting Informa-
tion for full spectroscopic characterizations). Overall, 3rd
generation, functional poly-azido dendrimer 4b was obtained
in 80% yield, for six successive synthetic steps, and in a
complete atom-economy fashion: no by-products (but so-
dium bromide, removed by the aqueous work ups) were pro-
duced. Moreover, the excess monomer was recovered (more
than 90% in each metal-free Click ligation), and no tedious
chromatography was performed. The use of solvent was min-
imal, and all reactions were performed at room temperature.
All together, this results show the extreme efficiency but also
practicality of this synthetic approach. The versatility of
metal-free, click ligation was illustrated with the synthesis of
two 4th generation dendrimers with various surface func-
tionalities: 5a results from the clicking of 1 to 4b (G3-N3),
similarly to the building of the previous generations. Den-
drimer 5a or G4-Br was obtained in a 94% yield, using the
simple precipitation procedure in diethyl ether. This den-
drimer presents 32 bromo moieties group at its periphery,
and a molecular weight of 9771.93 g molꢀ1. On top of pro-
ton and carbon NMR spectroscopy, MALDI-TOF mass spec-
trometry confirmed without ambiguity the perfect dendritic
architecture of 5a (no fragments corresponding to structural
defects due to incomplete reactions were observed).
FIGURE 2 GPC traces of bromo-terminated, generation 3 (4a;
black trace) and 4 (5a; dashed trace) dendrimers.
and 5a). The SEC-calculated molecular weights (3071 and
5319 g molꢀ1 for 4a and 5a, respectively) were found to be
well below the expected theoretical values (exact masses of
4699.91 and 9771.93 g molꢀ1 for 4a and 5a, respectively):
this phenomenon arises from the fact that the separation in
a SEC experiment relies on hydrodynamic volumes of macro-
molecules, which is a function of chain length for flexible
coils (such as the polystyrene standards used for calibra-
tion). However, dendritic molecules are ramified structures,
and thus exhibit a much larger mass per unit length: accord-
ingly, the true molecular masses should be much larger than
the observed MW determined by SEC, as observed previ-
ously.24 As bromo-alkyl moieties are amongst the more ver-
satile functional groups in organic synthesis (and provide an
easy access to the azido functionality for further click modifi-
cations), this 4th generation dendrimer presents itself as a
readily synthesized yet generic platform for subsequent deri-
vatization and access to functional dendritic architectures.
Similarly, the clicking of excess acetylene dicarboxylic acid to
4b yielded a 4th generation dendrimer 5b with 32 carbox-
ylic acid moieties on its periphery (G4-COOH). This den-
drimer was purified by a simple precipitation, at room tem-
perature, of the crude reactional mixture in diethyl ether (in
which the acetylenic diacid is very soluble). As dendrimer
solubility is mostly dictated by surface functionalities, the
presence of 32, ionisable carboxylic acid moieties brings
water-solubility of the perfectly well-defined macromolecule,
as well as the possibility of further bioconjugation using con-
ventional peptidic coupling conditions.
In summary, a highly efficient, divergent route to triazole
based dendrimers was developed. The process relies on a
metal-free, room temperature ligation of electronically acti-
vated alkynes to azides. Because of the extremely mild reac-
tion conditions, the process is virtually compatible to any
functional group. Moreover, the building of high molecular
weight dendrimers only requires a readily available, inexpen-
sive monomer, and the only by-product formed is sodium
bromide. Finally, simple purification procedures (either filtra-
tion through silica gel or precipitation) afforded high purity
Size exclusion chromatography (SEC) was performed on den-
drimer 5a and compared to the previous, bromo-terminated
3rd generation 4a (Fig. 2). In both cases, the technique
showed a mono-modal distribution, and a polydipersity
index characteristic of dendrimer structure (1.06 for both 4a
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dendrimers and permit the excess monomer to be recycled,
which should allow the methodology to be extended to large
scale production and applications where the absence of re-
sidual metal catalyst is of crucial importance.
flask. A catalytic amount of pTSA (0.51 g, 3 mmol) was
added, and the reaction mixture was refluxed with azeo-
tropic removal of the water produced during the ester for-
mation (Dean-Stark). After 26 h, the mixture was allowed to
cool to room temperature. The solvent was removed in
vacuo. The pale yellow residue was purified by chromatogra-
phy over a silica gel column, eluting with ethyl acetate:
hexanes (1:4; vol:vol) to afford 13.74 g of the title compound
(96%) as a colorless oil.
EXPERIMENTAL
Chemicals
Acetylenedicarboxylic acid (2-butynedioic acid; 95%,
Aldrich), 3-bromo-1-propanol (97%, Aldrich), para-toluene
sulfonic acid (98.5þ%, Aldrich), sodium azide (99.5þ%,
Aldrich), and anhydrous dimethyl sulfoxide (DMSO; 99.9þ%,
Aldrich) were used as received. 1,4-Bis(azidomethyl) ben-
zene was prepared as previously described.25 Solvents (tolu-
ene, diethyl ether, dichloromethane, and hexanes) were dried
over activated alumina or used as received (Reagent Grade).
NMR solvents (CDCl3, DMSO-d6) were obtained from Cam-
bridge Isotope Laboratories. All syntheses were carried out
in dry apparatus under a dry nitrogen atmosphere utilizing
conventional bench-top techniques (synthesis of BBBD 1), or
under normal atmosphere in glass scintillation vials for all
dendrimers (Fisherbrand). Water was purified by a Millipore
purification system (resistance ¼ 18.1 MX cm).
1H NMR (CDCl3, 600 MHz): d 2.23 (quint, 4H, 3J ¼ 6.0Hz);
3.47 (t, 4H, 3J ¼ 6.6Hz); 4.37 (t, 4H, 3J ¼ 6.0Hz); 13C NMR
(CDCl3, 150 MHz): d 28.79; 31.21; 64.66; 74.80; 151.57; HR-
MS: ES-positive mode: (m/z): 371.9458 (MþNH4þ) (calcu-
lated: 371.9446 (MþNH4þ)).
Synthesis of dendrimer G1-Br 2a: BBDM (1) (1.51g, 4.2
mmol) and 1,4-bis(azidomethyl) benzene (0.19 g, 1.0 mmol)
were introduced in a glass scintillation vial (15 ꢁ 45 mm)
with a small magnetic Teflon-coated stir bar. Under stirring,
the originally heterogeneous mixture quickly turns into a
single liquid phase. Deuterated chloroform (1 mL) was
added to prevent gelation and allow 1H NMR monitoring:
completion was reached in 6 h. The contents of the vial were
passed through a short silica gel column (performed in a 60
mL disposable syringe; 2.5 cm diameter, 8 cm height) eluting
with 1% methanol in DCM. Two sets of fractions were com-
bined: the first set contains the excess alkyne (Rf ¼ 0.88;
0.754 g, equivalent to 95% of the excess used; elution
required ꢂ50 mL of solvent), and the second set yielded the
generation 1 dendrimer 2a (Rf ¼ 0.21; 0.90 g, 99.0% yield;
elution required an additional 100–150 mL of solvent) as an
off white solid after evaporation of the volatiles in vacuo.
Additionally, as the TLC showed only the presence of excess
starting alkyne and dendrimer, it was possible to accelerate
even more the process: once the excess alkyne was eluted,
the column was simply flushed with the eluent by applying
pressure with the plunger of the syringe, allowing elution of
the dendrimer in less than 15 min.
Methods
Spectroscopic characterization of organic compounds: 1H
NMR Fourier spectra were recorded on a Bruker AC-200
(200 MHz) spectrometer or on a Bruker 600 AVANCE. Chem-
ical shifts for 1H NMR spectra are reported with respect to
the following standards: residual chloroform set at 7.26 ppm
and tetramethylsilane set at 0 ppm. 13C NMR Fourier spectra
were performed on a Bruker 600 AVANCE (at 150.30 MHz).
13C NMR spectra are reported with respect to the following
standard: chloroform set at 77.16 ppm. Coupling constants
(J) are recorded in Hertz (Hz). The abbreviations s ¼ singlet,
d ¼ doublet, t ¼ triplet, q. ¼ quartet, quint. ¼ quintuplet, dd
¼ doublet of doublets, m ¼ multiplet, are used in reporting
the spectra. Pneumatically-assisted electrospray ionization
mass spectrometry ESMS was performed on a Micromass
Quattro-LC triple quadrupole mass spectrometer with
dichloromethane, dichloromethane:methanol (50/50) or
methanol as the mobile phase at a flow rate of 15 mL/min,
with use of a Brownlee Microgradient syringe pump. Sam-
ples were dissolved in dichloromethane:methanol (50/50) or
pure methanol. Ammonia or NH4OAc was added for analysis
in negative ion mode; for analysis in the positive mode, for-
mic acid was added. Mass spectra were reported as percent
intensity (%) versus mass/charge (m/z) ratio. SEC was car-
ried out on a Waters 2695 separations module, equipped
with a Waters 2414 refractive index and Waters 2996 photo-
diode array detectors. Separation was achieved via 3 inline
4.6 mm ꢁ 25 cm Jordi fluorinated mixed bed columns. The
samples were run at 1 mL/min using a 99% THF/1% ACN
eluent and calibrated to polystyrene standards ranging from
580 Da to 3.1 million Da.
1H NMR (CDCl3, 600 MHz): d 2.18 (quint, 4H, 3J ¼ 6.0Hz);
3
3
2.31 (t, 4H, J ¼ 6.0Hz); 3.41 (t, 4H, J ¼ 6.0Hz); 3.51 (t, 4H,
3J ¼ 6.0Hz); 4.43 (t, 4H, 3J ¼ 6.0Hz); 4.49 (t, 4H, 3J ¼
6.0Hz); 5.79 (s, 4H); 7.27 (s, 4H); 13C NMR (CDCl3, 150
MHz): d 29.13; 29.31; 31.26; 31.63; 53.44; 63.73; 64.59;
128.85; 129.46; 134.84; 140.43; 158.30; 159.96; HR-MS: ES-
positive mode: (m/z): 896.9071 (MþHþ), calculated:
896.9093 (MþHþ) [Isotopic pattern, Relative intensity
100%: 900.9077 (found), 900.9056 (calculated)].
Synthesis of dendrimer G1-N3 2b: Dendrimer 2a (0.73g, 0.8
mmol) was dissolved in dry DMSO (6 mL) in a glass scintilla-
tion vial. A small magnetic Teflon-coated stir bar was added,
followed by sodium azide (1.06 g, 16.3 mmol). The mixture
was stirred at room temperature for 4 h, at which time 1H
NMR indicated completion of the reaction. The content of
the vial was poured into 50 mL of water, and extracted 5
times with DCM (1 ꢁ 50 mL and 4 ꢁ 25 mL). The aqueous
phase was then salted, and extracted again with 2 ꢁ 25 mL
of DCM. The combined organic phase was washed twice with
Synthesis
Synthesis of BBBD 1: Acetylenedicarboxylic acid (4.56 g,
40.0 mmol), 3-bromo-1-propanol (16.68 g, 120.0 mmol) and
benzene (50 mL) were placed in a 100 mL round-bottomed
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2012, doi: 10.1039/C2CS35062A; (o) G. R. Newkome, C.
Shreiner, In Designing Dendrimers; C., Sebastiano; C. Paola; P.,
Fausto, Eds.; John Wiley & Sons, Inc., 2012, pp 57–93; (p) D.
Astruc, L. Liang, A. Rapakousiou, J. Ruiz, Acc. Chem. Res.
2012, 45, 630–640.
water, dried over sodium sulfate, filtered, and the volatiles
were removed in vacuo without heating, yielding the title
compound (0.585 g, 96.0% yield) as yellow viscous oil.
1H NMR (CDCl3, 600 MHz): d 1.91 (quint., 4H, 3J ¼ 6.0Hz);
2.03 (quint., 4H, 3J ¼ 6.0Hz); 3.38 (t, 4H, 3J ¼ 6.0Hz); 3.47
8 P. Antoni, M. J. Robb, L. Campos, M. Montanez, A. Hult, E.
3
3
3
€
Malmstrom, M. Malkoch, C. J. Hawker, Macromolecules 2010,
(t, 4H, J ¼ 6.0Hz); 4.36 (t, 4H, J ¼ 6.0Hz); 4.43 (t, 4H, J ¼
6.0Hz); 5.78 (s, 4H); 7.26 (s, 4H); 13C NMR (CDCl3, 150
MHz): d 27.92; 28.19; 47.74; 48.04; 53.40; 62.85; 63.75;
128.79; 129.54; 134.84; 140.39; 158.32; 159.93; HR-MS:
ES-positive mode: (m/z): 749.2761 (MþHþ), calculated:
749.2729 (MþHþ).
43, 6625–6631.
9 H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int.
Ed. 2001, 40, 2004–2021.
10 G. Franc, A. Kakkar, Chem. Commun. 2008, 5267–5276.
11 P. Wu, A. K. Feldman, A. K. Nugent, C. J. Hawker, A. Scheel,
ꢀ
B. Voit, J. Pyun, J. M. J. Frechet, K. B. Sharpless, V. V. Fokin,
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ACKNOWLEDGMENTS
12 K. L. Killops, L. M. Campos, C. J. Hawker, J. Am. Chem.
Soc. 2008, 130, 5062–5064.
The authors thank the Natural Sciences and Engineering
Research Council of Canada for financial support of this research.
13 T. Kang, R. J. Amir, A. Khan, K. Ohshimizu, J. N. Hunt, K.
~
Sivanandan, M. I. Montanez, M. Malkoch, M. Ueda, C. J.
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