This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 4483–4485 4483

Cite this: Chem. Commun., 2012, 48, 4483–4485

Facile synthesis of fluorescent dye labeled biocompatible polymers viaimmortal ring-opening polymerizationw

Wei Zhao,ab

Yang Wang,ab

Xinli Liuaand Dongmei Cui*

a

Received 14th February 2012, Accepted 7th March 2012

DOI: 10.1039/c2cc31061a

A highly efficient strategy for synthesizing ‘‘clean’’ fluorescent

dye-labeled biocompatible polymers was established by employing

a rare-earth metal catalyst via immortal ROP.

Dye-labeled polymers containing fluorescent (fluorophore) or

non-fluorescent (chromophore) compounds at specific sites of

polymer chains such as the chain-end and the junction between

blocks have gained much attention for their wide applications in

optical imaging,1,2 signal amplification in biological diagnostics,3

light-harvesting and photochromic materials4 as well as in fluores-

cence studies about intra- and inter-polymer chain associations,

conformation and dynamics of polymer chains.5,6 Remarkable

advances have been achieved concerning vinyl monomers via

anionic polymerization or living radical polymerization to give

dye-labeled polymers.7 In contrast, strategies available for dye-

labeled biodegradable polyesters from heterocyclic monomers

such as lactones, lactams, glycolides, carbonates and lactides are

very limited.

Polyesters have been widely applied in pharmaceutics and

medical fields as well as tissue engineering and tissue repair

systems owing to their excellent biocompatible and biodegradable

properties as well as their versatile mechanical properties.8

Therefore, research has focused on synthesizing such polymers

with different stereochemistry, comonomer incorporation and

linear/grafted block, star-shaped, dendrimer and hyperbranch

architectures. However, little attention is given to precisely

incorporating functional dye molecules into these polymer

backbones, which has become of particular scientific and

application relevance. For example, when PLAs are used for

packing materials, decorations, fibers and textiles, from an

aesthetic point of view, the coloration under mild conditions

without damage of molecular weight, tensile strength and

elongation at break is a necessary and important process

before ultimate consumables can be produced and sold on

the market. When PLA materials are applied as drug delivery

devices, a detailed knowledge of the final fate of the macro-

molecular vectors is often required. One important tracking

approach is to precisely label the polymer chains with fluorescent

compounds and in situ monitor their diffusion within tissue and

live cells using established techniques such as fluorimetry and

confocal fluorescence microscopy.9 Very recently, McGowan

et al. successfully combined the synthesis and coloration of

PLA fiber by using dyed aluminium catalysts via coordination

ROP of rac-lactide (rac-LA)10 (Scheme 1, method (1)).

Herein, we wish to report a highly efficient strategy suitable

for synthesizing dye-labeled (a-chain ends) polyesters from

e-caprolactone (e-CL), racemic b-butyrolactone (b-BL) and

rac-LA etc. heterocyclic esters via immortal polymerization by

using a small amount of rare-earth metal complex as the

precursor and an excess of a fluorescent dye containing hydro-

xyl function as the chain transfer agent. The resultant polyesters

have not only a precisely located fluorescent label but also

designable molecular weight, narrow distribution and high

stereoregularity (Scheme 1, method (2)). Noteworthy is that,

during the polymerization, nearly all o-chain ends of polymer

chains are automatically capped with hydroxyls which is facile

for the further functionalization of obtained polymers. This

strategy breaks ‘‘one catalyst–one polymer chain’’ restriction of

the conventional coordination polymerization and provides a

convenient one-pot approach to ‘‘clean’’ dye-labeled polymers

with very low metal residue that is requisite for special fields. To

the best of our knowledge, this is the first example of catalytic

preparation of well-defined and clean dye-labeled biopolymers

with rare-earth metal-based complexes.

Fluorescent dye A bearing a hydroxyl group was synthesized

by modifying the commercially available, near-infrared dye

Scheme 1 Two different dye-labeled methods by employing coordination

catalysts.

a State Key Laboratory of Polymer Physics and Chemistry,Changchun Institute of Applied Chemistry, Chinese Academy ofSciences, 5625 Renmin street, Changchun 130022, China.E-mail: dmcui@ciac.jl.cn; Fax: +86 431 85262774;Tel: +86 431 85262773

bGraduate School of the Chinese Academy of Sciences, Beijing100039, China

w Electronic supplementary information (ESI) available: Experimental pro-cedures and copies of 1HNMR spectra of complexes 1–4 and a spectrum ofthe oligomer for end group study. See DOI: 10.1039/c2cc31061a

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4484 Chem. Commun., 2012, 48, 4483–4485 This journal is c The Royal Society of Chemistry 2012

rhodamine 6G, which has an exceptionally high quantum

yield (40.9) and wide applications in biomedical imaging

(Scheme S1 and Fig. S1, ESIw).11 For the first time, dye A was

employed to react stoichiometrically with O,N,N,O-tetradentate

Salan lutetium alkyl complex 1. Metathesis reaction between

metal alkyl moiety Lu–CH2SiMe3 in 1 and a hydroxyl group of

A generated a fluorescent dye-labeled Lu–alkoxide counterpart

(3) by releasing TMS (tetramethyl silane), exclusively as shown in

Scheme 2. The reaction was clean and highly selective and no

ligand dissociation was observed as evidenced by the NMR

monitoring result (Fig. 1).

To our delight, complex 3 showed high activity towards the

ROP of rac-LA in THF at room temperature, in which the

Lu–OA group acted as the initiator (Table 1, entries 1–3).

Repeated coordination–insertion of rac-LA into Lu–OA active

species gave the fluorescent A labeled PLA. The 1H NMR

spectrum of such an oligomeric PLA sample confirmed that the

fluorescent A group attaches to one PLA chain end (Fig. 2),

which is further supported by the fluorescence behavior study of

the obtained PLA (Fig. S6, ESIw). The molecular weights of the

resultant PLAs determined by GPC, Mn,GPC, were very close to

those of theoretical valuesMn,calcd (calculated based on monomer

conversion and the assumption that a single fluorescent

dye-labeled PLA chain is produced per Lu metal center), mean-

while the polydispersity indices were extremely low (PDIo 1.06),

indicative of a living polymerization mode. Moreover, all PLA

samples possessed very high heterotacticity with Pr = 0.99 which

confirmed further that the A reacted with the lutetium-alkyl

moiety selectively whilst the Salan ligand remained untouched

and kept bonding to lutetium ions to govern the selectivity via its

steric environment.

Gratifyingly, addition of an excess of A (based on Lu) to the

polymerization system did not arouse termination as usually

happened. In contrast, the increase in [A] only led to a regular

decrease in the molecular weight of PLA obtained, and no

broadened molecular weight distribution was observed, indicative

of an immortal polymerization.12 Varying the [A]/[Lu] molar

ratio in a broad range from 5 : 1 to 600 : 1, the polymerization

proceeded smoothly in a living mode and retained the immortal

characteristics to give PLAs with variable molecular weights

(Mn = 0.16 � 104–1.19 � 104), narrow molecular weight

distributions (PDI = 1.03–1.07) and especially high hetero-

tacticity (Pr 4 0.97) (entries 4–10). This suggested that

complex 3 was very stable in the presence of a large amount

of fluorescent dye A without ligand dissociation from the

metal center. Meanwhile A behaved as a chain transfer agent,

which mediated a rapid and reversible exchange reaction with

Lu–OA (or Lu–OCHCH3CO–(LA)n–OA). Thus, the resultant

PLAs were automatically end-capped with the –OH group at

one end, which was involved in the polymerization cycle and

played the same role as fluorescent dye A. Therefore when the

polymerization was performed at a LA-to-Lu ratio of 6000 : 1 in

the presence of 600 equivalents of A (vs. [Lu]) to completeness, a

high productivity of up to 6000 molLA per molLu was successfully

achieved and 600 dye-labeled PLA chains grew from each active

metal center (entry 10). To our knowledge, such performance of

the ROP of LA in terms of productivity and chain-transfer

efficiency ranks among the best results reported thus far.Moreover,

when an isoselective aluminium complex 2 was employed

instead of complex 1, the ROP of rac-LA could also proceed

in an immortal manner to afford dye-labeled isotactic PLAs

as anticipated albeit at a high temperature (entries 11–13).

However, the activity is much lower than that of complex 1.

To establish the possible generality of the above strategy, ROPs

of e-CL and racemic b-BL were performed with 1 in combination

with dye A, which provided dye-labeled PCL and syndiotactic-

enriched PBBL (Pr = 0.83), respectively (entries 14–18). In the

case of b-BL ROP, the immortal nature remained.

Scheme 2 One-pot synthesis of a-fluorescence labeled o-hydroxylated polyesters via immortal ROP by using complexes 1 and 2 and fluorescent dye A.

Fig. 1 1H NMR spectrum of complex 3 (300 MHz, CDCl3, 25 1C).

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 4483–4485 4485

In summary, we have reported a new and potentially general

applied strategy for the facile synthesis of fluorescent dye-labeled

polyesters via immortal ROPs of heterocyclic monomers by using

a catalytic amount of metal-based complexes with an excess of

hydroxylated dye compounds. This strategy breaks the ‘‘one

catalyst–one dye-labeled polymer chain’’ limitation that a series

of ‘‘clean’’ dye-labeled polyesters have been obtained in the

form of low metal residue, designed molecular weight, narrow

distributions, excellent a-dye labeled and o-hydroxyl fidelity,and high stereoregularity.

We are grateful for financial support from the National

Natural Science Foundation of China for project No.

20904051 and 51021003.

Notes and references

1 J. Callahan and J. Kopecek, Biomacromolecules, 2006, 7, 2347.2 K. Kim, M. Lee, H. Park, J. H. Kim, S. Kim and H. Chung, J. Am.Chem. Soc., 2006, 128, 3490.

3 M. T. Charreyre, B. Mandrand, J. M. G. Martinho, P. Relogio andJ. P. S. Farinha, WO2007003781, 2007.

4 M. Chen, K. P. Ghiggino, A. W. H. Mau, E. Rizzardo,S. H. Thang and G. J. Wilson, Chem. Commun., 2002, 2276.

5 P. Relogio, J. M. G. Martinho and J. P. S. Farinha,Macromolecules,2005, 38, 10799.

6 J. Duhamel, Acc. Chem. Res., 2006, 39, 953.7 M. Beijad, M. T. Charreyre and J. M. G. Martinho, Prog. Polym.Sci., 2011, 36, 568.

8 (a) A. Finne and A. C. Albertsson, Biomacromolecules, 2003,3, 684; (b) A. Kowalski, A. Duda and S. Penczek,Macromolecules,2000, 33, 689; (c) Y. Kikkawa, H. Abe, T. Iwata, Y. Inoue andY. Doi, Biomacromolecules, 2002, 3, 350.

9 (a) K. D. Jensen, A. Nori, M. Tijerina, P. Kopeckova andJ. Kopecek, J. Controlled Release, 2003, 87, 89; (b) S. C. W.Richardson, K.-L. Wallom, E. L. Ferguson, S. P. E. Deacon,M. W. Davies, A. J. Powell, R. C. Piper and R. J. Duncan,J. Controlled Release, 2008, 127, 1; (c) S. L. Mangold,R. T. Carpenter and L. L. Kiessling, Org. Lett., 2008, 10, 2997.

10 R. O. MacRae, C. M. Pask, L. K. Burdsall, R. S. Blackburn,C. M. Rayner and P. C. McGowan, Angew. Chem., Int. Ed., 2011,50, 291.

11 T. Nguyen and M. B. Francis, Org. Lett., 2003, 5, 3245.12 N. Ajellal, D. M. Lyubov, M. A. Sinenkov, G. K. Fukin,

A. V. Cherkasov, C. M. Thomas, J. F. Carpentier andA. A. Trifonov, Chem.–Eur. J., 2008, 14, 5440.

Table 1 Immortal polymerization of rac-lactide in the presence of fluorescent dye A

Runa Monomer Catalyzer [Cat.]/[A]/[Mono.] Time/min Conv.b (%) Mn,calcdc (10�4) Mn,GPC

d (10�4) Mw/Mnd Pr/Pm

e

1 rac-LA 1 1/1/500 60 91 6.60 6.63 1.05 0.99/0.012 rac-LA 1 1/1/1000 60 80 11.58 12.03 1.06 0.99/0.013 rac-LA 1 1/1/1500 60 36 7.83 8.00 1.05 0.99/0.014 rac-LA 1 1/5/500 60 86 1.28 1.19 1.04 0.99/0.015 rac-LA 1 1/10/500 60 85 0.66 0.64 1.06 0.98/0.026 rac-LA 1 1/20/500 60 88 0.36 0.39 1.03 0.99/0.017 rac-LA 1 1/50/500 60 84 0.19 0.18 1.06 0.99/0.018 rac-LA 1 1/100/1000 270 85 0.17 0.16 1.06 0.98/0.029 rac-LA 1 1/300/3000 480 100 0.19 0.20 1.07 0.99/0.0110 rac-LA 1 1/600/6000 480 100 0.19 0.21 1.07 0.97/0.0311f rac-LA 2 1/1/200 1440 40 1.20 1.32 1.02 0.17/0.8312f rac-LA 2 1/5/200 1440 50 0.33 0.36 1.03 0.16/0.8413f rac-LA 2 1/10/200 1440 52 0.19 0.21 1.06 0.17/0.8314g rac-BBL 1 1/1/300 30 100 2.63 2.52 1.19 0.83/0.1715g rac-BBL 1 1/10/300 30 100 0.30 0.28 1.10 0.82/0.1816g rac-BBL 1 1/30/300 30 100 0.13 0.16 1.09 0.83/0.1717h CL 1 1/1/300 5 100 3.47 3.60 1.18 —18h CL 1 1/1/600 10 100 6.89 7.12 1.20 —

a Polymerizations were performed under N2 in THF at 25 1C, [LA]0 = 0.69 M. b Obtained from 1H NMR analysis. c Calculated by ([Mono.]0/

[A]0) � MMono. � X (X = Conv.) + MA.d Determined by GPC in THF using polystyrene standards (the obtained Mn for PLA and PCL were

corrected with 0.58 and 0.56, respectively). e Pr/Pm of PLA is the probability of racemic/mesomeric linkages between monomer units determined

from the methane region of the homonuclear decoupled 1H NMR spectrum, Pr + Pm = 1. f Polymerizations were performed under N2 in THF at

70 1C, [LA]0 = 0.69 M. g Polymerizations were performed under N2 in CH2Cl2 at 25 1C, [BBL]0 = 1.16 M, Pr/Pm of PBBL (entries 14–16) is the

probability of racemic/mesomeric linkages between monomer units determined by the 13C{1H} NMR spectrum, Pr + Pm = 1. h Polymerizations

were performed under N2 in THF at 25 1C, [CL]0 = 1.46 M.

Fig. 2 1H NMR spectrum of dye-labeled oligomeric PLA (400 MHz,

CDCl3, 25 1C; *: LA). Conditions: [LA]0 = 0.69 M, [LA]0 : [Lu]0 : [A]0 =

20 : 1 : 1, THF, 97% conversion, Tp = 25 1C.

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