Nitrone-mediated radical coupling reactions: A new synthetic tool exemplified on dendrimer synthesis

Article abstract of DOI:10.1039/c1cc10322a

A synthetic strategy employing nitrones as radical spin traps is presented on the example of the efficient generation of novel dendrimers via a combination of radical and classical 'click' chemistry.

Full text of DOI:10.1039/c1cc10322a

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Nitrone-mediated radical coupling reactions: a new synthetic tool
exemplified on dendrimer synthesisw
Edgar H. H. Wong,ab Ozcan Altintas,a Martina H. Stenzel,b Christopher Barner-Kowollik*a
and Thomas Junkers*c
Received 17th January 2011, Accepted 16th March 2011
DOI: 10.1039/c1cc10322a
A synthetic strategy employing nitrones as radical spin traps is
presented on the example of the efficient generation of novel
dendrimers via a combination of radical and classical ‘click’
chemistry.
We have earlier demonstrated that this nitrone-mediated
radical coupling (NMRC)5–7 works very efficiently with
macromolecules. In here, we wish to demonstrate that the
same reaction also allows for excellent proficiency in non-
polymer reactions. To highlight the efficiency, we have chosen
to use the NMRC reaction for the build-up of a dendrimer.
For the dendrimer synthesis, a combination of radical
(NMRC) and ‘click’8 chemistries (copper catalyzed azide
alkyne cycloaddition, CuAAC) was employed in a divergent
growth approach. Since nitrones are able to react with two
radical species resulting in the doubling of functional groups
with the newly generated alkoxyamine situated in a mid-
position, branch points are readily created. This allows for
the generation of higher order structures and thus such a
dendrimer synthesis approach is an ideal example representing
the innovation of nitrone radical chemistry. In addition, the
extremely well-defined structure of dendrimers is associated
with unique physical properties. Thus, these entities have
found many useful applications especially in the biomedical
field,9–11 yet generating such materials is synthetically often
challenging. The NMRC reaction will therefore add to and
complement the current efficient synthesis methodologies.12
As mentioned above, the NMRC reaction is built on our
experience with the recently developed enhanced spin capturing
polymerization (ESCP),6,7,13–15 which was inspired by earlier
studies employing nitrones by our colleagues.16 The dendrimer
synthesis is based on three starting compounds as given in
Scheme 2: (i) a trisnitrone core; (ii) an AB monomer that bears
an azide functionality at one end and a 2-bromopropionate
group at the other (which when activated by a copper/ligand
catalyst system generates acrylate-typed radicals that are to be
captured by the nitrone) and (iii) a CD2 monomer carrying one
alkyne moiety and two nitrone functions. Both AB and CD2
monomers are designed to have sufficiently long alkyl chain
spacers (11 CH2 groups) between the functional groups to
ensure there is enough flexibility while minimizing steric
hindrance during the radical coupling reactions.
Nitrones constitute an efficient class of compound capable of
acting as both 1,3-dipoles in cycloaddition reactions1–3 or in
radical reactions as spin trap agents.4 It is through cycloaddition
reactions that nitrones have found synthetic application. It
comes, however, as a surprise that their ability to selectively
trap radicals is largely under-utilized in chemical syntheses
even though nitrones can potentially be applied as a synthetic
device in radical chemistry. Upon addition of radicals,
nitrones form nitroxides in high yields, which can subsequently
react with a second radical species forming an alkoxyamine
(see Scheme 1). In such a radical coupling reaction, a multi-
functional compound is derived with two potential functional
units stemming from the radical species situated at both ends
as well as a precisely centered-alkoxyamine group which may
carry a secondary functionality (e.g. alkynyl, hydroxyl,
aldehyde, etc.) in a mid-chain position. Thus, the radical spin
capturing reaction may provide an attractive avenue for the
synthesis and fast assembly of complex molecular architectures.
Scheme 1 Spin trapping reaction between radicals Rꢀ and a nitrone
to form an alkoxyamine.
a Preparative Macromolecular Chemistry, Institut fur Technische
¨
Chemie und Polymerchemie, Karlsruhe Institute of Technology
(KIT), Engesserstr. 18, 76128 Karlsruhe, Germany.
E-mail: christopher.barner-kowollik@kit.edu;
Fax: +49 721-60845740; Tel: +49 721-608-45641
b Centre for Advanced Macromolecular Design (CAMD),
School of Chemical Engineering, The University of New South
Wales, Sydney, NSW 2052, Australia
c Institute for Materials Research, Polymer Reaction Design Group,
Universiteit Hasselt, Agoralaan, Gebouw D, B-3590 Diepenbeek,
Belgium. E-mail: thomas.junkers@uhasselt.be; Fax: +32 1126-8399;
Tel: +32 1126-8318
As indicated in Scheme 2, the first generation dendrimer,
G1-[N3]6, was synthesized by reacting the trisnitrone core with
an excess of AB monomer (5 eq. per nitrone) under typical
NMRC reaction conditions, i.e. in the presence of 1 eq. of
copper powder and the ligand PMDETA for 4 h at 60 1C. The
integrity of the azide functionality remains intact under these
w Electronic supplementary information (ESI) available: Experimental
details, complete synthetic procedures, full 1H-NMR spectra and mass
spectra obtained from (SEC)-electrospray ionization-mass spectro-
metry analysis. See DOI: 10.1039/c1cc10322a
c
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Chem. Commun., 2011, 47, 5491–5493 5491

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Fig. 1 SEC traces of the formed dendrimers.
synthesis strategies such as the ones that are based on
thiol-yne12a,17 and thiol-ene12b,c reactions. The present NMRC
approach is best comparable to thiol-yne methodologies since
both methods allow for addition of two moieties via a radical
process. Thiol-yne is known to be also efficient and fast. It
should, however, be noted that the synthesis of functional
nitrones is relatively simple and thus easily applicable.
Scheme 2 Overall employed strategy in the synthesis of up to third
generation dendrimers via repetitive NMRC and ‘click’ reactions.
conditions. After the removal of the copper complex, the
product was further purified by column chromatography
and subsequently used directly in the next step without
the need for any protection/deprotection reaction step. The
second generation, G2-[Nit]12, was obtained via CuAAC of the
azide groups of G1-[N3]6 with the alkyne of the CD2 monomer
(1.1 eq. of alkyne per azide). It is worth mentioning that
although the nitrones may potentially undergo cycloaddition
reactions too with the alkynes, this side product was not
detected in the product mixture and it may thus be assumed
that the azides react faster and therefore preferentially with the
alkynes compared to nitrone–alkyne cycloaddition reactions
in this particular system. The copper catalyst is removed by
simply percolating the G2-[Nit]12 over a column of basic
alumina. No further purifications were necessary apart from
excess monomer removal via dialysis in ethanol/chloroform.
In the next step, each of the twelve nitrone groups on the
periphery of G2-[Nit]12 was further functionalized to yield
G3-[N3]24 via NMRC with only slightly increased amounts of
AB monomer (8 eq.) to ensure maximum functionalization.
An excess of monomer was only employed to ensure high
reaction rates, the same reactions could also be carried out
with less equivalents of the AB monomer provided the NMRC
The successful formation of the dendrimers via the described
approach was followed via size exclusion chromatography
(SEC) (see Fig. 1). With each generation, a clear shift towards
higher molecular weights (correlated by the decrease in retention
times) is observed. The distributions are, as indicated by the
measured PDI (see Table 1), practically monodisperse indicating
that all functionalities are converted in each reaction step.
Table 1 also lists the theoretical average molecular weights,
Mn, of each dendrimer structure as well as those determined by
SEC, 1H-NMR and mass spectrometry (MS) analysis. The
values measured by SEC are—not surprisingly—inaccurate
given that their values are based on a polystyrene calibration.
Therefore, they do not reflect the actual molecular weights.
Nonetheless, SEC remains an excellent technique in providing
consistent qualitative analysis. The values determined by
1H-NMR and MS on the other hand are more accurate and
thus in close agreement with the theoretical values. For the MS
data of G2 it should be noted that the mass was calculated on
the basis of multiple charged species, hence the obtained
value is closer to the isotope-averaged mass rather than the
monoisotopic value, therefore explaining the relatively large
deviation between the experiment and theoretical value.
Fig. 2 shows the 1H-NMR spectra of the end group regions
of the synthesized dendrimers. An important point to
note based on the NMR spectra is that the formation of
diastereomers caused by the alkoxyamines may give the false
impression that the products are impure. The overlap of
reaction was optimized by—for instance—using
a less
activated copper/ligand system.5 As will be shown in the
following, the obtained third generation dendrimer is of high
purity and no indication for a loss of functionality is given.
Thus, although we did not attempt to proceed to higher
generations in the framework of this study, no reason is seen
why the reaction could not be driven to higher generations.
However, it must be noted that the kinetics of the current
NMRC reactions were not optimized as stated above and thus
lower than optimum yields may be obtained when the formed
dendrimers are to be extrapolated to higher generation
structures. Nevertheless, the overall approach required minimal
column purification. In addition, each functionalization step
resulted directly in the increase in dendrimer generations, thus
placing the approach among other highly efficient dendrimer
Table 1 Theoretical and experimental average molecular weights
(in g mol–1) of the dendrimers shown in Scheme 2. SEC relative to a
poly(styrene) calibration
Dendrimer
Theoretical
1H NMR
MS
SECa
G1-[N3]6
G2-[Nit]12
G3-[N3]24
2386.58
8185.94
14 632.57
2487
8874
16 827
2387.1
8189.5
—
3600 (1.006)
11 600 (1.007)
17 400 (1.011)
a
The values in brackets are polydispersity indices, PDI.
c
5492 Chem. Commun., 2011, 47, 5491–5493
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the successful synthesis of the targeted dendritic structures.
The synthesis method only requires a minimum number of
purification procedures and no protection/deprotection steps,
thus demonstrating the viability of nitrone radical chemistry in
organic synthesis.
C. B.-K. is grateful for continued support from the
Karlsruhe Institute of Technology (KIT) in the context of
the Excellence Initiative for leading German universities.
T.J. acknowledges funding from the Fonds Wetenschappelijk
Onderzoek (FWO). E.H.H.W. and O.A. are thankful for
postgraduate scholarships from UNSW and the Islamic
Development Bank (IDB), respectively. M.H.S. acknowledges
receipt of a Future Fellowship from the ARC.
Notes and references
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Fig. 2 1H-NMR spectra of the end group regions evidencing the
chemical transformations as the dendrimers increase in generations.
The dotted lines indicate where the protons in the a-position of the
azide group and the nitrone protons lie in their respective regions. The
full NMR spectra can be found in the ESI.w
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think likewise. In spite of this, the products are in fact pure
and the chemical transformations of the dendrimers as they
progressively increase in generations were successfully monitored
by the disappearance/reappearance of the key protons
associated with the functional groups. In the synthesis of
G1-[N3]6, the nitrone proton at 7.63 ppm originating from
the trisnitrone core clearly disappeared and a new peak
(3.20–3.28 ppm) corresponding to the protons on the a
position of the azide groups occurred. The nitrone protons
reappeared as the azide end groups undergo CuAAC reactions
to yield G2-[Nit]12. Along with this nitrone-characteristic
proton, a new peak belonging to the proton of the triazole
ring was formed at 7.65 ppm. When subjecting the second
generation dendrimer to NMRC reactions, the nitrone protons
disappear again while the a-protons of the azides reoccur, thus
confirming the formation of G3-[N3]24.
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c
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