Utilising 14C-radiolabelled atom transfer radical polymerisation initiators

Article abstract of DOI:10.1039/b913294e

¹⁴C-radio-initiated atom transfer radical polymerisations allow direct monitoring of the fate of initiating species.

Full text of DOI:10.1039/b913294e

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14
Utilising C-radiolabelled atom transfer radical polymerisation
initiatorsw
a
a
a
b
´ ¨
Mark Long, David W. Thornthwaite, Suzanne H. Rogers, Gwenaelle Bonzi,
Francis R. Livensc and Steve P. Rannard*b
Received (in Cambridge, UK) 3rd July 2009, Accepted 10th September 2009
First published as an Advance Article on the web 28th September 2009
DOI: 10.1039/b913294e
14C-radio-initiated atom transfer radical polymerisations allow
direct monitoring of the fate of initiating species.
labelling of the polymer end-groups also avoids statistical
label incorporation, i.e. all labelled chains carry equal radio-
activity. Here, we describe the first radiolabelled ATRP via the
generation of 14C-labelled 2-bromoisobutyric acid; the synthesis
of two variants of an ATRP initiator, each with 14C-labels at a
different site; the utilisation of this initiator in ambient
alcoholic-ATRP and new observations, revealed through the
ability to monitor selectively the fate of initiating groups.
There are two potential strategies to 14C-label ATRP
initiators; the reaction of 1 with 14C-labelled alcohols,
Scheme 1A, and the reaction of 14C-labelled 2-bromoisobutyric
acid with any hydroxyl compound, Scheme 1C.
Since its earliest reports,1a–c atom transfer radical polymerisation
(ATRP) has grown to become a leading controlled radical
polymerisation technique in many academic and industrial
research groups. The advent of aqueous and alcoholic
ATRP1d–f significantly broadened the scope of the technique,
allowing water-soluble polymers to be controllably synthesised
at ambient temperatures under protic solvent conditions.
Mechanistically, ATRP has been studied to determine reaction
pathways,2a enabling many of the complex architectures that
have been reported.2b–f
The reaction of 1 with benzyl alcohol to form benzyl
2-bromoisobutyrate was conducted under conventional,
unlabelled conditions to establish the optimum experimental
techniques for high recovered yields (93%). To minimise the
use of 14C-labelled benzyl alcohol (0.02 moles), 2, the reaction
was repeated (Scheme 1A, see ESIw) at a smaller scale (20%)
The almost ubiquitous 2-bromoisobutyryl bromide, 1, may
be reacted with any hydroxyl to generate an ATRP initiating
site,3a allowing control of polymer chain-end structure.
Together with controlled polymer synthesis, this has allowed
systematic changes of structure and architecture and enabled
the fundamental study of factors affecting specific polymer
behaviour; for example, stimuli-responsive chain assembly.3b,c
Many investigations of polymer deposition, drug delivery and
polymer nanoparticle formation have also been reported4
although accurately quantifying the action, fate or even the
presence of polymer in these studies remains a challenge. In
several cases, the polymer has been dye-labelled5 to aid
observation but, by the very nature of the labelling, this
technique modifies the polymer composition, solubility, response
to stimuli and surface interactions.
Radiolabels6 have been utilised to aid polymer detection in
studies such as mucoadhesion6a or pharmaceutical delivery.
This is often a post-treatment of pre-formed polymers, for
example tritiation of labile protons,6b,c chelation of heavy
metal radioisotopes (e.g. 64Cu),6d methylation of amines6e
using 14C-methyl iodide or iodination6f,g using 125I. These
have the potential to modify polymer properties and beha-
viour. In contrast, substitution of 14C for existing carbons7
within the polymer building blocks (monomers/initiators) is
probably the least intrusive labelling strategy. Selective
a Unilever Research and Development Port Sunlight Laboratories,
Quarry Road East, Bebington, Wirral, UK CH63 3JW
b Department of Chemistry, University of Liverpool, Crown Street,
Liverpool, UK L69 7ZD. E-mail: srannard@liv.ac.uk;
Fax: +44 (0)151 794 3501; Tel: +44 (0)151 794 3501
c School of Chemistry, The University of Manchester, Oxford Road,
Manchester, UK M13 9PL
Scheme 1 Strategies for synthesising 14C-labelled ATRP initiators,
(A) esterification of 14C-labelled benzyl alcohol, (B) synthesis of
14C-labelled 2-bromoisobutyric acid, (C) reaction of 14C-labelled
2-bromoisobutyric acid with benzyl alcohol.
w Electronic supplementary information (ESI) available: Experimental
methodology, GPC analysis, NMR spectra, R-TLC data. See DOI:
10.1039/b913294e
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to form
3 (87%) as confirmed by nuclear magnetic
spectroscopy (NMR) and radio thin-layer chromatography,
R-TLC (Fig. 1A) (97% radiochemical yield, 3.015 mCi mgꢁ1
specific activity, 96% radiochemical purity). 14C-labelled
2-bromoisobutyric acid is required to allow a more general
approach to forming labelled ATRP initiators. In order to
avoid placing the radiolabel directly near a labile ester,
through the use of 14CO2 and Grignard approaches, we chose
to introduce the label via 14C-methylation of diethyl 2-methyl-
malonate, 4, using 14C-methyl iodide to form 5, Scheme 1B. As
is typical within radiochemical reactions at this scale, a
proportion of unlabelled methyl iodide was also used in order
to ensure the optimum reaction of the 14C-labelled material
(see ESIw). Hydrolysis and subsequent decarboxylation of 5
led to the synthesis of 14C-labelled potassium isobutyrate, 7,
which underwent bromination to form the 14C-labelled
2-bromoisobutyric acid, 8, in an overall 35% recovered chemical
yield based on diethyl 2-methylmalonate (54% radiochemical
yield, 15.6 mCi mgꢁ1 specific activity, 99% radiochemical
purity). All steps were conducted under non-labelled
conditions prior to radiochemical synthesis (see ESIw). The
reaction of 8 with 1,10-carbonyl diimidazole, 9, formed the
bromoacid imidazolide, 10, which was reacted with benzyl
alcohol to form the 14C-labelled benzyl 2-bromoisobutyrate,
11 (56% radiochemical yield, 0.36 mCi mgꢁ1 specific activity,
98% radiochemical purity) (Fig. 1B). Comparison of the
R-TLCs of 3 and 11 showed identical behaviour under optimised
TLC conditions (see ESIw, Fig. S6/S16). 3 exhibited 98.3% of
the total measured radioactivity within a single region (region
2, Fig. 1A), 0.9% within the baseline and 0.8% within a small
decomposition peak; 11 showed 98.2% radioactivity in a
single region (0.9% baseline; 0.9% decomposition).
Fig. 2 Monomer and polymer structures formed during this study:
2-hydroxypropyl methacrylate (HPMA), 12; unlabelled poly(HPMA),
13; 14C methylene-labelled poly(HPMA), 14; 14C methyl-labelled
poly(HPMA), 15.
The benzyl alcohol derived, radiolabelled initiators (3, 11)
and an analogous unlabelled initiator were used to initiate the
ambient temperature methanolic ATRP of 2-hydroxypropyl
methacrylate (HPMA), 12, producing polymers 13, 14 and
15 (Fig. 2). Several polymerisations using each initiator under
identical conditions with targeted number average degree of
polymerisation (DPn) of 50 monomer units were conducted.
Near identical kinetics, conversion, DPn and polydispersity
were obtained for all polymers using each initiator variant
(see ESIw, Fig. S17), confirming the absence of any observable
impact on polymerisation from either radiolabel position.
Gel permeation chromatography (see ESIw, Fig. S18)
suggested a DPn of approximately 65 monomer units (relative
to PMMA standards); ATRP often yields higher chain lengths
than targeted.1 Several reports suggest the loss of initiator, or
the presence of termination reactions, in the initial stages of
the polymerisation2 when the concentration of Cu(II) species is
particularly low and prior to established equilibrium between
the dormant and active radical centres. 1H NMR analyses
gave an observed DPn of approximately 40 monomer units
suggesting residual unreacted initiator within the purified
sample. Conversions 495% were achieved for all polymerisations
suggesting an actual DPn 4 47 units.
The presence of a radiolabelled initiator residue allows a
high sensitivity analysis of the resulting polymers and study of
the fate of the initiator. A purely radioactivity-based detection
method renders all unlabelled chemical species invisible to the
analysis, so all signals from a radio-initiated ATRP must be
related to reactions of the initiator. Initiators labelled at
different sites (3 and 11) allow verification that degradation
reactions, such as hydrolysis of the initiator, are not leading to
observed radio species. R-TLC typically measures radio-
chemical purity (Fig. 1) but here it has been utilised to study
polymers without normal purification techniques and at high
monomer conversion (496%; target DPn = 10, 25 and
50 monomer units). When the samples were eluted with
THF, no separation was observed (see ESIw, Fig. S19).
A mixture of diethyl ether and acetic acid (90/10) led to an
excellent separation of unreacted radio-initiator from the bulk
sample (Fig. 3). The resulting R-TLCs can be divided into
three clear regions: initiator, polymer and intermediate. The
boundaries chosen for each region were derived from the pure
initiator R-TLCs (Fig. 1A and B) and the apparent limits of
the polymer separation at DPn = 50 (Fig. 3A and B).
Fig. 1 Radio thin layer chromatography of 14C labelled 2-bromo-
isobutyrate. (A) methylene-labelled initiator 3; (B) methyl-labelled
initiator 11. Insets show background radioactivity. (Eluent:
Et2O–CH3CO2H 90/10 v/v.)
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We recognise that a benzyl ester initiator is not ideal for the
polymerisation of 12 in methanol, probably leading to the
observed poor initiator efficiencies, however the ability to
quantify the apparently unreacted initiator and species derived
from the initiator is of value within mechanism studies. It is
important to note that radiopolymers have a limited ‘‘lifetime’’
for study due to their physical degradation however we intend
to develop this approach to derive new quantitative insight
across various polymerisation techniques.
We thank the Royal Society for an Industry Fellowship
(SR) and Unilever for financial support.
Notes and references
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radioactivity. (Eluent: Et2O–CH3CO2H 90/10 v/v.)
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This journal is The Royal Society of Chemistry 2009
6408 | Chem. Commun., 2009, 6406–6408