9062 Chem. Commun., 2012, 48, 9062–9064 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Commun., 2012, 48, 9062–9064

Combining chemoenzymatic monomer transformation with

ATRP: a facile ‘‘one-pot’’ approach to functional polymersw

Changkui Fu,aLei Tao,*

aYun Zhang,

aShuxi Li

aand Yen Wei*

ab

Received 28th June 2012, Accepted 20th July 2012

DOI: 10.1039/c2cc34633h

A facile ‘‘one-pot’’ chemoenzymatic-ATRP has been successfully

developed through the combination of copper-catalytic ATRP and

enzyme-catalytic monomer transformation reactions.

‘‘One-pot’’ synthesis is a strategy to improve the chemical

reaction efficiency whereby a reactant is sequentially subjected

to reactions in just one reactor. A ‘‘one-pot’’ strategy is much

desired by chemists due to its avoiding arduous separation and

purification of the intermediates, improving chemical yield,

as well as saving time and resources. In polymer chemistry,

‘‘one-pot’’ processes have been achieved by exquisite combination

of some compatible reactions with polymerization, resulting in

the concerted and facile syntheses of elegant polymers with

pre-designed functionalities and structures.1–5 However, some

of such ‘‘one-pot’’ polymerizations are carried out under harsh

conditions (i.e. complex catalysts/reactants or high temperature),

which greatly counteracts the advantages of the ‘‘one-pot’’ system.

On the other hand, enzymes are regarded as green catalysts for

a variety of reactions. Compared with conventional synthetic

catalysts, enzymes appear to be more environmentally friendly

under milder conditions with high efficiency and high selectivity.6

Thus, combining enzymatic reactions with the polymerization

process represents an alternative promising approach for the

development of facile synthesis of sophisticated polymers.

Atom transfer radical polymerization (ATRP) is a potent

methodology to prepare well-defined polymers. Because of its

mild reaction conditions, general applicability of monomers and

controllable features, ATRP has been proven to be a powerful

tool for the synthesis of polymers with designed molecular

weight, composition, architecture as well as functionality.7–15

Previous studies have suggested that some enzymatic reactions

can co-exist with the ATRP process.16 An outstanding example is

the ‘‘one-pot’’ synthesis of copolymers in supercritical CO2 by

combining the enzymatic ring-opening polymerization (ROP) of

e-caprolactone (e-CL) with the ATRP of (meth)acrylates. The

enzyme–chem-dual catalytic system is robust under reaction

conditions and both catalysts (enzyme and copper) tolerate

each other, leading to one step synthesis of well-defined block

or graft copolymers.17–20 However, besides the combination of

enzyme mediated ROP and ATRP process, there are few reports

referred to new ‘‘one-pot’’ chemoenzymatic polymerization tandem

systems. To take full advantage of enzymes, the excellent green

catalysts, deep insight and extension of the scope of enzyme–

chem-dual catalytic polymerization are still in need to develop

efficient and versatile synthetic strategies to functional

polymers.

Herein, we demonstrate a novel ‘‘one-pot’’ polymerization

strategy by combination of lipase-catalytic monomer transforma-

tion and copper-mediated ATRP to prepare polymers with

designed molecular weight, composition, and transformed side

groups. This facile ‘‘one-pot’’ synthetic strategy involves an in situ

enzymatic transesterification accompanying with the living

radical polymerization process. The synthetic strategy we have

applied is summarized in Scheme 1.

Commercially available Novozym 435, Candida antarctica

lipase B (CALB), was used to catalyze the transesterification

between fluoridated monomer 2,2,2-trifluoethyl methacrylate

(TFEMA) and alcohols (ROH) to generate the target monomer

R methylacrylate (RMA). The new formed RMA participates in

the ATRP process sequentially as a comonomer with TFEMA,

i.e., the initiator ethyl 2-bromoisobutyrate (EBiB) induces the

copolymerization of TFEMA and the gradually generated

RMA, resulting in copolymers with transformed –R side groups.

The excellent tolerance of many functional groups and the

controllable polymerization process of ATRP allow for the

Scheme 1 ‘‘One-pot’’ chemoenzymatic-ATRP for polymer synthesis

via in situ enzymatic monomer transformation.

aDepartment of Chemistry, Tsinghua University, Beijing 100084,P. R. China. E-mail: leitao@mail.tsinghua.edu.cn;Tel: +86-010-62792604

bKey Lab of Organic Optoelectronic & Molecular Engineering ofMinistry of Education, Department of Chemistry,Tsinghua University, Beijing 100084, P. R. China.E-mail: weiyen@tsinghua.edu.cn

w Electronic supplementary information (ESI) available: Detailedexperimental description and results including 1H NMR spectra,GPC results etc. See DOI: 10.1039/c2cc34633h

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 9062–9064 9063

coherent cooperation of the enzyme catalytic system. To achieve

the ‘‘one-pot’’ chemoenzymatic-ATRP process, the transesterifica-

tion rate should match well with that of chain propagation of

polymerization. Ideally, considerable new monomer RMA should

be quickly generated and participate in the ATRP process together

with the acyl donor monomer. Thus, TFEMA is chosen as the

acyl donor monomer for the in situ monomer transformation due

to its much higher reactivity for enzymatic transesterification with

alcohols than other (meth)acrylates such as methyl methacrylate

(data not shown). Typically, the chemoenzymatic-ATRP of

TFEMA in the presence of hexanol was selected as an example

in the next detailed elucidation. The polymerization was

carried out at 45 1C using CuBr–4,40-dinonyl-2,20-dipyridyl

(dNbpy) as catalyst–ligand for ATRP. Since 2,2,2-trifluoro-

ethanol, the by-product from the transesterification of TFEMA

with alcohols, was found to hinder greatly the ATRP process

(data not shown), an equivalent amount of triethylamine (TEA)

was added into the reaction system to ensure the smooth

polymerization. Kinetics studies of the reaction revealed that

two stages exist during the ‘‘one-pot’’ chemoenzyamtic-ATRP

process (Fig. 1a). In the first stage (initial three hours), the

enzymatic transformation of TFEMA to hexyl methacrylate

(HMA) quickly proceeded, resulting in almost no TFEMA left

in the polymerization system after 3 h (Fig. S1b, ESIw).Meanwhile, 29% of total monomers polymerized to form

the poly(TFEMA)-co-poly(HMA) copolymer (Fig. 1a), which

contained approximately 78% of poly(HMA) proportion in

the copolymer composition (Fig. S2 and S3, ESIw).After the first stage, the monomers remaining in the system

were almost entirely HMA (Fig. S1b, ESIw). Thus, the secondstage could be regarded as the controlled homopolymerization

of HMA, and the polymerization continuously proceeded to

high monomer conversion (24 h, B84%, Fig. 1a). The ATRP of

HMA exhibited linear pseudo-first-order kinetic plots (Fig. 1a), the

molecular weights increased linearly with monomer conversions

and all the polymers had narrow molecular weight distributions

(PDI B 1.35) (Fig. 1b and 2a), indicative of a well-controlled

ATRP process in the presence of enzyme.

The 1H NMR spectrum of the final obtained polymer is

shown in Fig. 2b. The peaks corresponding to the ester groups

of poly(TFEMA) and poly(HMA) appeared at 4.30 ppm and

3.90 ppm, respectively. According to the integral ratio of the

peaks at 4.30 ppm and 3.90 ppm, the fraction of poly(HMA)

contained in the obtained polymer was calculated to be

approximately 90%, suggesting that the final obtained polymer

is akin to a poly(HMA) homopolymer with a short domain of

gradient poly(TFEMA)-co-poly(HMA) copolymer as the head

(Fig. 2b and Fig. S3, ESIw).Immobilized enzyme can be facilely isolated for reuse after

reactions. Moreover, immobilized CALB is highly stable and

can be operated at elevated temperature for thousands of hours

without significant loss in activity.21 In current work, the retained

enzyme activity after polymerization was analyzed through

enzymatic transesterification of 4-nitrophenyl acetate (4-NPA)

with methanol.22 As shown in Table 1 (No. 1), the enzyme

catalyst maintained nearly complete activity (93%) compared

with the pristine enzyme, further suggesting the excellent

compatibility of the enzymatic reaction with ATRP. The easy

separation and excellent enzyme activity maintenance after

the ATRP process provide additional advantage to the chemo-

enzymatic-ATRP system for future large scale manufacture.

Furthermore, versatility of the chemoenzymatic-ATRP system

was also examined using various alcohols as substrates (Table 1).

For primary alcohols such as hexanol, ethanol (EtOH), benzyl

alcohol (BzOH) and poly (ethylene glycol) methyl ether (mPEG350),

the transesterification of TFEMA cooperated well with ATRP

while the enzyme retained excellent activity (Table 1, No.1–4), The1H NMR analyses of the obtained polymers indicated that the

principal polymer compositions (B75–90%) are the poly(RMA)

(Fig. 3). Moreover, all obtained polymers have predesigned mole-

cular weights and narrow PDIs (B1.40), indicating well-controlled

ATRP processes.

Using secondary alcohols such as iso-propanol (iPA) in the

chemoenzymatic-ATRP system, approximately 56% of TFEMA

Fig. 1 ‘‘One-pot’’ chemoenzymatic-ATRP containing in situ transfor-

mation from TFEMA to HMA: (a) transesterification conversion,

monomer conversion and the kinetic curve versus polymerization time;

(b) molecular weight and PDI of the polymer versus monomer conver-

sion. Novozym 435= 0.50 g; [EBiB] = 12.5 mM; [dNbpy] = 18.75 mM;

[CuBr] = 6.25 mM; [TFEMA]0 = 1.0M; [Hexanol]0 = 1.0 M; [TEA] =

1.0 M in 6.0 mL of toluene at 45 1C.

Fig. 2 (a) GPC curves of polymers during the polymerization;

(b) 1H NMR spectrum (CDCl3) of poly(TFEMA)-co-poly(HMA)

after purification.

Table 1 ‘‘One-pot’’ chemoenzymatic-ATRP of TFEMA andalcoholsa

No. AlcoholConv.b

(%)RMAc

(%) Mnd PDIe

Retained enzymeactivityf (%)

1 Hexanol 84 90 160 00 1.35 93 � 32 BzOH 44 86 9000 1.40 83 � 53 EtOH 73 75 8000 1.41 70 � 04 mPEG350 56 80 6000 1.26 80 � 45 iPA 31 61 6200 1.73 92 � 26 tBA 29 0 3900 1.50 100 � 0

a Novozym 435 = 0.50 g; [EBiB] = 12.5 mM; [dNbpy] = 18.75 mM;

[CuBr] = 6.25 mM; [TFEMA]0 = 1.0 M; [ROH]0 = 1.0 M; [TEA] =

1.0 M in 6.0 mL of toluene at 45 1C. b Calculated by 1H NMR.c The proportion of RMA in the polymer calculated by 1H NMR.d Determined byGPC. e Determined byGPC. f Determined by enzymatic

hydrolytic activity of 4-NPA.

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9064 Chem. Commun., 2012, 48, 9062–9064 This journal is c The Royal Society of Chemistry 2012

was converted into iso-propyl methacrylate (iPMA) within

initial 3 h and there was still 15% of TFEMA remaining in the

polymerization system after 5 h (Fig. S4a, ESIw), indicating a

comparatively slow enzymatic monomer transformation rate,

which is likely due to the steric hindrance of the iso-propyl

group.23 The enzyme also retained B92% activity after poly-

merization (Table 1, No. 5). However, the ATRP system

seemingly lost controllable character. The total polymerized

monomer wasB31% after 24 h, and the obtained polymer has

broad PDI (B1.73) with 61% of poly(iPMA) content in the

resulted poly(TFEMA)-co-poly(iPMA) copolymer (Fig. S4b,

ESIw). This phenomenon is probably attributed to the slow

generation of iPMA and the intrinsic low reactivity of iPMA

in such a quite low temperature ATRP system.

When tertiary alcohols such as tert-butanol (tBA) was used

as the substrate, the transesterification scarcely occurred despite

the enzyme retaining 100% activity during the polymerization

(Table 1, No. 6), the purified polymer was a homopolymer of

poly(TFEMA) with PDI B1.50 (Table 1, No. 6, Fig. S5, ESIw),corroborating the fact that tertiary alcohols are poor substrates

for CALB.24–27

In conclusion, a novel ‘‘one-pot’’ chemoenzymatic-ATRP

has been successfully developed by the combination of lipase-

catalytic transesterification and copper mediated ATRP. This

new synthetic strategy involved the tandem copolymerization

of the original monomer TFEMAwith enzymatically transformed

RMA. The enzyme CALB demonstrated selectivity to different

alcohol substrates. When primary alcohols were used, the enzyme

cooperated well with ATRP, appeared to be efficient under

ATRP conditions, and maintained nearly complete activity

after polymerization. The in situ monomer transformation

allowed us to obtain copolymers possessing different trans-

formed –R side groups depending on the substrate alcohols.

Considering the facile and versatile features, this ‘‘one-pot’’

chemoenzymatic-ATRP system could provide a general meth-

odology for sophisticated polymer synthesis and might have

potential applications in various areas such as biological and

material sciences.

This research was supported by the National Science Foun-

dation of China (21104039, 21134004) and the National 973

Project (no. 2011CB935700).

Notes and references

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S. M. Howdle, J. Am. Chem. Soc., 2005, 127, 2384.18 S. Villarroya, K. J. Thurecht, A. Heise and S. M. Howdle, Chem.

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Fig. 3 The 1H NMR spectra of polymers through the ‘‘one-pot’’

chemoenzymatic-ATRP of TFEMA and primary alcohols: ethanol

(a), benzyl alcohol (b) and mPEG350 (c).

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