One-pot tandem living radical polymerisation-Huisgens cycloaddition process ("click") catalysed by N-alkyl-2-pyridylmethanimine/Cu(I)Br complexes

Article abstract of DOI:10.1039/b500558b

Azide terminally functional poly(methyl methacrylate)s (M_n = 4000-6000, PDI = 1.21-1.28) have been prepared by living radical polymerization and successfully reacted with alkynes in a Huisgen cycloaddition (click) reaction in one pot using the same catalyst for both processes. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b500558b

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One-pot tandem living radical polymerisation–Huisgens cycloaddition
process (‘‘click’’) catalysed by N-alkyl-2-pyridylmethanimine/Cu(I)Br
complexes{
Giuseppe Mantovani, Vincent Ladmiral, Lei Tao and David M. Haddleton*
Received (in Cambridge, UK) 13th January 2005, Accepted 17th February 2005
First published as an Advance Article on the web 2nd March 2005
DOI: 10.1039/b500558b
Azide terminally functional poly(methyl methacrylate)s
5 4000–6000, PDI 5 1.21–1.28) have been prepared by
We reasoned that a process that combines Cu(I)-catalysed
Huisgen cycloaddition and LRP could allow for a one-pot
synthesis of a wide variety of products spanning from new
a-functional and grafted/star shaped polymers to biohybrid
materials. Our synthetic strategy involved the synthesis of
appropriate azido-initiators, polymerisation of methacrylic mono-
mers in the presence of a Cu(I)-based catalyst followed by a
subsequent in situ ‘‘clicking’’ to functional terminal alkynes. It is
noted that azide terminally functional polymers have been
prepared previously by transformation of terminal halides with
(M
n
living radical polymerization and successfully reacted with
alkynes in a Huisgen cycloaddition (click) reaction in one pot
using the same catalyst for both processes.
‘‘Click chemistry’’ is a general term that identifies a class of
chemical transformations with a number of attractive features
including excellent functional-group tolerance, high yields and
good selectivity under mild experimental conditions. This is
coupled with the use of readily available reagents and usual
25
sodium azide. However, in this case quantification proved
difficult and as termination events always occur in living radical
polymerization, of any type, the functional initiator approach is
preferred.
1
,2
avoidance of chromatographic purification of products. Among
these reactions, the Huisgen 1,3-dipolar cycloaddition has been
receiving increasing interest following the emergence of enormous
improvement in regioselectivity and yields in the presence of
copper(I)-based catalysts. An acceleration of the reaction rate of
approximately seven orders of magnitude has been observed using
The Cu(I)/Cu(II)–iminopyridine complexes employed in LRP
are reported to be distorted tetrahedral N
bipyramid N –Cu(II)X derivatives, although many coordinating
products, monomer, solvent and additives can also coordinate to
4
–Cu(I) and trigonal
4
3,4
Cu(I). This discovery has led to its application in a many
26,27
5,6
the metal centre affecting the reactivity of the catalytic system.
processes including the synthesis of therapeutics, protein-based
7–11
biohybrids,
12
sugar arrays, dendrimers
13,14
We first verified that these copper complexes were active catalysts
for Huisgen-type cycloadditions. Reaction of 1-octyl azide and
propargyl alcohol in toluene at 70 uC, using 10% copper catalyst
and functional
15–18
polymers.
The overall reaction is a cycloaddition of an alkyne
and an organic azide to give a five-membered 1,2,3-triazole. The
resulting ‘‘clicked’’ products can even be obtained via in situ
generation of the required organic azides from organic halides–
28
(Cu(I)Br–Cu(II)Br –N-ethyl-2-pyridylmethanimine 0.95 : 0.05 : 2)
2
gave complete conversion of the reactants in less than one hour,
with exclusive formation of the 1,4-disubstituted adduct. In the
absence of the catalyst a conversion of 35% was reached after 2
days, with a 1.5 : 1.0 ratio between the two possible regioisomers,
NaN
the need to handle organic azides. The proposed mechanism for
copper(I)-catalysed reaction involves the addition of
Cu(I)-acetylide to an azide in a stepwise sequence, giving a five-
3
in the presence of an alkyne and a copper catalyst, avoiding
19
a
a
3
in favour of the 1,4, in agreement with previous reports.
3,20
Initiators (3a and 3b) were prepared as shown in Scheme 1. The
azido-alcohol intermediates (2) were obtained by treatment of
membered vinyl cuprate which yields the triazole product. The
required Cu(I) catalysts are usually prepared by either in situ
reduction of Cu(II) salts or by use of an appropriate Cu(I) complex
3
bromo and tosyl alcohols with NaN in refluxing acetone–water
13,16
3,4
8,10,21
solution. Subsequent acylation of (2) with 2-bromoisobutyryl
with triphenylphosphine,
ligands.
mono or polydentate
nitrogen
Transition-metal mediated living radical polymerisation (TMM-
LRP, often termed ATRP) has rapidly developed as a way to new
functional materials. This process shares a number of important
features with click chemistry including robustness, versatility and
excellent tolerance towards many functional-groups, including
22,23
water.
We envisaged the possibility that these two reactions
could share the same catalyst and in particular we focused our
24
attention towards Cu(I)Br–iminopyridine catalytic systems.
Scheme 1 Reagents and conditions: a) NaN
3
, acetone–water, reflux, b)
{ Electronic Supplementary Information (ESI) available: experimental
procedure and characterisation of prepared compounds. See http://
2
-bromoisobutyryl bromide, Et N, Et O, 0 uC to ambient temperature, c)
3
2
i. methyl methacrylate, N-alkyl-2-pyridylmethanimine–Cu(I)Br; ii.
RCMCH.
www.rsc.org/suppdata/cc/b5/b500558b/
*D.M.Haddleton@warwick.ac.uk
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bromide and triethylamine gave the desired azido-ester initiators
3a and 3b). Polymerisation of methyl methacrylate using (3a and
b) as the initiators gave good first order kinetic plots, regardless of
(
3
the length of the linker connecting the azide moiety and the
polymer backbone (Fig. 1).
The initiating efficiency of (3b) was found to be higher (close to
100%) than that observed for (3a), a result that may be ascribed to
the different steric effects on the initiating centre. The a-functional
polymers obtained from (3a) also showed a lower content of azide
chain-ends (75–86% depending on the conditions employed) in
contrast to the apparent 100% content for the polymers obtained
Fig. 2 Dilute solutions of purified ‘‘clicked’’ polymers (5b) with dyes (6)
and (7), taken under visible and UV light (l 5 350 nm) respectively.
1
from (3b) in toluene at 90 uC. H NMR analysis revealed that this
for the octyl azide–propargyl alcohol adduct. All of the click
reactions were complete after stirring the reaction mixture at 70 uC
overnight. Some free iminopyridine ligand was detected during the
cycloaddition step, ascribed to a certain degree of coordination of
the triazole product to the metal. The sequential LRP–Huisgens
cycloaddition process proved to be efficient in a range of solvents
decrease in the azide content occurs mainly at the early stages of
the polymerisation and that was observed even at reduced
polymerisation rates achieved by both reducing the amount of
2
Cu(I) catalyst and by addition of Cu(II)Br to the reaction mixture.
This behaviour may be related to an intramolecular cyclisation
involving the azide moiety and the propagating centre and will be
the subject of further investigation.
including toluene, anisole, and poly(ethylene glycol) (M y400,
n
29
PEG400). The efficiency of the click reaction was further
investigated in the presence of a range of model functional alkynes
including the diaza (6) and coumarin (7) dyes (Fig. 2). The
observed reactivity did not differ significantly from that observed
where propargyl alcohol was employed as the ‘‘alkyne’’ substrate,
giving the a-functional polymers in close to 100% yields.
The reactivity of the a-functional azide polymers was demon-
strated by the addition of propargyl alcohol to the polymerisation
mixture at high monomer conversion (87–95%) and monitoring
the disappearance of the -CH N signal (triplet at 3.2 and 3.4 ppm
2
3
1
for (4a) and (4b) respectively) in the H NMR. The final ‘‘clicked’’
polymers showed a pattern of signals analogous to that observed
In summary, we report the first example of a one-pot tandem
copper(I)-catalysed sequential LRP–Huisgens cycloaddition pro-
cess. The synthetic protocol developed for the required azido-
initiators is very general and can allow for easy modification both
the nature and the size of the spacer between the azido moiety and
the initiating centre. The Cu(I)Br–iminopyridine complexes
employed have shown great versatility, catalysing efficiently both
of the processes, under a number of different experimental
conditions. This approach constitutes a very powerful tool for
the one-pot synthesis of a number of new materials such as new
grafted polymers, functional surfaces and bioconjugates.
This research was supported by a Marie Curie Intra-European
Fellowship within the 6th European Community Framework
Programme (GM, MEIF-CT-2003–501305). The authors would
like to thank the University of Warwick (VL and LT) for funding
1
and Dr Adam Clarke for his help with the online H NMR
experiments and Emma Melia for useful discussions.
Giuseppe Mantovani, Vincent Ladmiral, Lei Tao and
David M. Haddleton*
Department of Chemistry, University of Warwick, Coventry, UK
CV4 7AL. E-mail: D.M.Haddleton@warwick.ac.uk;
Fax: +44 24 7652 8267; Tel: +44 24 7652 3256
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090 | Chem. Commun., 2005, 2089–2091
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Chem. Commun., 2005, 2089–2091 | 2091