Synthesis of Polycaprolactone

8/16/2019 Synthesis of Polycaprolactone

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with others (polyethylene, polypropylene, natural rubber, poly-

(vinyl acetate), and poly(ethylene–propylene) rubber).

PCL biodegrades within several months to several years

depending on the molecular weight, the degree of crystallinity

of the polymer, and the conditions of degradation.6–14 Many

microbes in nature are able to completely biodegrade PCL.6

The amorphous phase is degraded first, resulting in an increase

in the degree of crystallinity while the molecular weightremains constant.9 Then, cleavage of ester bonds results in

mass loss.7,14 The polymer degrades by end chain scission

at higher temperatures while it degrades by random chain

scission at lower temperatures (Fig. 1).13 PCL degradation

is autocatalysed by the carboxylic acids liberated during

hydrolysis7 but it can also be catalysed by enzymes,

resulting in faster decomposition.11 While PCL can be

enzymatically degraded in the environment, it cannot be

degraded enzymatically in the body.8

PCL has uses in different fields such as scaffolds in tissue

engineering,9,14–16 in long-term drug delivery systems7,10,11 (in

particular contraceptives delivery8), in microelectronics,17 as

adhesives,13 and in packaging.8 Its wide applicability and

interesting properties (controlled degradability, miscibility

with other polymers, biocompatibility and potential to be

made from monomers derived from renewable sources) makes

PCL a very useful polymer if its properties can be controlled

and it can be made inexpensively. A large number of catalysts

and catalytic systems, spanning virtually the whole periodic

table have been investigated. It is therefore paramount to have

a good understanding and overview of the different catalysts

and catalytic systems that have been studied to drive new

developments in catalysis (whether organic-, metal- or

enzyme-based) or chose the appropriate system to obtain the

polymer with the desired characteristics. The former would be

of interest to anyone working on catalysis, whereas the latter is

more directed towards polymer chemists. This review aims

to be a reference work that can be used for this purpose.

Knowledge of ineffective systems is of equal importance and

they are described in the ESI.w

Preparation of the monomers

A number of microorganisms oxidise cyclohexanol into adipic

acid (Scheme 1).18 In this process, both e-CL and 6-hydroxy-

hexanoic acid are intermediary products. Industrially, e-CL

is produced from the oxidation of cyclohexanone by peracetic

acid (Scheme 2).19

Table 1 Properties of PCL

Properties Range Ref.

Number average molecular weight(M n/g mol

1)530–630000 —

Density (r/g cm3) 1.071–1.200 1,3–6Glass transition temperature (T g/1C) (65)–(60) 3–5, 7 and 8Melting temperature (T m/1C) 56–65 3–8Decomposition temperature (/1C) 350 9

Inherent viscosity (Zinh/cm3 g

1) 100–130 5Intrinsic viscosity (Z/cm3 g1) 0.9 1Tensile strength (s/MPa) 4–785 3, 5, 6 and 8Young modulus (E /GPa) 0.21–0.44 3 and 5Elongation at break (e/%) 20–1000 1, 3, 5, 6 and 8

Fig. 1 Cleavage of the polymeric chains during the degradation of PCL.

Scheme 1 Oxidation of cyclohexanol to adipic acid in Acinetobacter sp. strain SE19, adapted from Thomas et al .18

This journal is c The Royal Society of Chemistry 2009 Chem. Soc. Rev., 2009, 38, 3484–3504 | 3485

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Polymerisation

There are two methods to prepare PCL: the condensation of 6-hydroxycaproic (6-hydroxyhexanoic) acid and the ring-

opening polymerisation (ROP) of e-CL.

Polycondensation

A large number of patents describe the preparation of aliphatic

polyesters from hydroxycarboxylic acids.20–24 Braud et al.25

synthesised PCL oligomers by polycondensation of 6-hydroxy-

hexanoic acid under vacuum—thereby removing the water

produced during the reaction and displacing the equilibrium

towards the formation of the polymer. The reaction was

performed without the addition of catalyst and was complete

in 6 h at a temperature that was gradually increased from 80 to

150 1C.

Polymerisation of 6-hydroxycaproic acid using lipase

from Candida antarctica under vacuum gave rise to

polymers with an average molecular weight of 9000 g mol1

and a polydispersity under 1.5 in 2 days.26 Using lipase

from Pseudomonas sp. at 45 1C to polymerise ethyl

6-hydroxyhexanoate resulted in polymers with an average

molecular weight of 5400 g mol1 and a polydispersity under

2.26 after 20 days with 82% monomer conversion.27 Ethanol

was produced as a byproduct, which influenced the equilibrium,

but it could be removed under vacuum.

Only a few papers describe the preparation of PCL by

polycondensation in detail. ROP gives a polymer with a higher

molecular weight and a lower polydispersity. As a consequence,

ROP is the preferred route and will be discussed in more detail

in the following section.

Ring-opening polymerisation

1. General mechanisms. Four main mechanisms for the

ROP of lactones exist, and they depend on the catalyst:

anionic, cationic, monomer-activated and coordination–

insertion ROP.

a Anionic ROP. Anionic ROP (Scheme 3) involves the

formation of an anionic species which attacks the carbonyl

carbon of the monomer. The monomer is opened at the

acyl–oxygen bond and the growing species is an alkoxide.28

The main drawback of this method is the occurrence of

significant intramolecular transesterification, also called

‘‘back-biting’’, in the later stages of the polymerisation. This

results either in low molecular weight polymers, if the

polymerisation is stopped before back-biting can occur, or in

cyclic polymers.

b Cationic ROP. Cationic ROP (Scheme 4) involves theformation of a cationic species which is attacked by the

carbonyl oxygen of the monomer through a bimolecular

nucleophilic substitution (SN2) reaction.28

c Monomer-activated ROP. Monomer activated ROP

(Scheme 5) involves the activation of the monomer molecules

by a catalyst, followed by the attack of the activated monomer

onto the polymer chain end.30,31

d Coordination–insertion ROP. Coordination–insertion

ROP (Scheme 6) is the most common form of ROP. It is

actually a pseudo-anionic ROP. The propagation is proposed

to proceed through the coordination of the monomer to the

Scheme 2 Production of e-caprolactone from cyclohexanone at Solvay.19

Scheme 3 Mechanism of the initiation step for anionic ROP, adapted from Khanna et al .29

Scheme 4 Mechanism of the initiation step for cationic ROP, adapted from Khanna et al.29 and Stridsberg et al .28

Scheme 5 Mechanism of the initiation step for the monomer-activated ROP, adapted from Kim et al.31 and Endo.30

3486 | Chem. Soc. Rev., 2009, 38, 3484–3504 This journal is c The Royal Society of Chemistry 2009

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catalyst and the insertion of the monomer into a metal–oxygen

bond of the catalyst. During propagation, the growing chain is

attached to the metal through an alkoxide bond.28

2. Transesterification side-reactions. During ROP of e-CL

using an initiator and a catalyst, both intermolecular trans-

esterification (Scheme 7) and intramolecular transesterification

(Scheme 8) can occur as side reactions. These reactions are

generally encountered during the later stages of polymerisation,

particularly at high temperature. It results in broadening of the

polydispersity, and loss of control of the polymerisation.

Catalysts used for ROP and reaction conditions

Three different catalytic systems are described: metal-based,

enzymatic, and organic systems (the latter section also mentions

small inorganic acids). A concise representation of allmentioned systems, and others, can be found in the ESI,w

following the same sequence as the text—their inclusion in the

body of this manuscript would hamper readability. Published

ineffective systems can also be in found in the ESI.w

ROP catalysed by metal-based compounds

Different authors use different terms to describe the metal-

based compounds which take part in the ROP of lactones.

Some authors use catalysts, others use initiators, initiating

systems or catalytic systems. Indeed, the metal-based com-

pound must be regenerated in the termination step to be a true

catalyst, and this does not always occur, thereby keeping the

polymeric chain ‘‘alive’’. As a consequence, some people recoilfrom calling them ‘‘catalysts’’. For the sake of consistency

in this review, we decided to call metal-based compounds

‘‘catalysts’’ and alcohols and amines ‘‘initiators’’. However,

sometimes, only one compound is used, mainly when a part of

the compound initiates the reaction (generally the alkoxide

part), while another part catalyses it (generally the metal

centre). In this case, the more appropriate term ‘‘catalyst–

initiator’’ is used.

1. Alkali-based catalysts. Alkali metal-based catalysts

(ESIw Table 1.1) showed some activity.32 These catalysts are

ionic compounds and the ROP mechanism is anionic. As a

consequence, polymerisation is not well controlled due to

transesterification. Moreover, alkali-based compounds

have a tendency to form aggregates, which decreases their

solubility.32

Bhaw-Luximon et al.33 polymerised e-CL in dioxane using

lithium diisopropylamide (LDA, ESIw Table 1.1, entry 1). The

polymerisation is proposed to proceed through an anionic

mechanism (Scheme 9).33 Completion of polymerisation was

reached after only a few minutes at 25 1C and a medium

molecular weight polymer was obtained (M n = 5700 g mol1

when [e-CL]/[LDA] = 50).

Phenyl lithium (ESIw Table 1.1, entry 2) led to high molecular

weight polymers after a few hours at 170 1C.35 Yuan et al.36

used cyclopentadienyl sodium (ESIw Table 1.1, entry 3) in bulk

and in non-polar solvents to obtain number average molecular

weights up to 130 000 g mol1. In polar solvents, only oligomers

were obtained. No cyclopentadienyl groups were present on the

polymeric chain ends and the polymerisation is said to proceed

through deprotonation of the monomer (Scheme 10).

Mingotaud et al.37 polymerised e-CL with different catalysts

in organic solvents and in supercritical carbon dioxide

(scCO2). Tert-butoxyl potassium (ESIw Table 1.1, entry 4)

was one of the catalysts tested. The conversion is lower for

scCO2, indicating the occurrence of side reactions between the

anionic species and carbon dioxide.

2. Alkaline earth-based catalysts. Catalysts based on

alkaline earth metals are very attractive because of their high

activity and low toxicity.32 The most commonly used alkaline

earth metals are magnesium and calcium. Magnesium, the

most abundant alkali earth metal, is essential to plants

and animals, and is therefore biologically benign.38 As a

consequence, it is an interesting metal to use in the synthesis

of polymers for biomedical applications.

Alkyl-containing magnesium complexes (ESIw Table 1.2,

entries 1–6) resulted in high molecular weight polymers with a

low to moderate polydispersity.39 The polymerisation is said

to be initiated by alkyl transfer into the monomer. Applying

magnesium alkoxide complexes (ESIw Table 1.2, entries 7 and 8)

to the ROP of e-CL gave rise to medium to high molecular

weight polymers (M n = 6300 to 54 200 g mol1) with low to

Scheme 7 Intermolecular transesterification reaction during the polymerisation of PCL.

Scheme 8 Intramolecular transesterification reaction during the polymerisation of PCL.

Scheme 6 Mechanism of the initiation step for coordination–insertion ROP, adapted from Khanna et al.29 and Stridsberg et al .28


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medium polydispersity (PDI = 1.06 to 1.35).40 The complex

from entry 7 led to faster polymerisation than the catalyst

from entry 8. This was attributed to the steric bulkiness of

complex 8, which sped up the reaction rate. Indeed, more

bulky ligands interact with the initiator and provide a steric

barrier to prevent side reactions.41 The polymerisation is

initiated via insertion of the alkoxy group into the monomer.

Shueh et al.42 investigated a magnesium aryloxide as a

catalyst (ESIw Table 1.2, entry 9). The linear relationship

between the monomer : initiator ratio and the molecular

weight of the polymer suggests a ‘‘living’’ character to the

polymerisation. No intramolecular transesterification, leading

to the formation of macrocycles, was found to occur.

Like magnesium, calcium is essential to animals and is

benign, and, therefore, very attractive as a catalyst. Zhong et al.

investigated a calcium-based system for the ROP of e-CL

(ESIw Table 1.2, entries 12a–12c).43 The molecular weight

distribution was found to be wide (PDI up to 4) but in the

presence of an alcohol, the polymerisation becomes controlled

(PDI close to 1) and first order in the monomer. The mechanism

of the reaction involves a rupture of the acyl–oxygen bond of

the monomer and the insertion into the Ca–O bond of the

calcium alkoxide (Scheme 11).

Piao and co-workers44,45 used calcium ammoniate

(ESIw Table 1.2, entry 13–15). The first step of the mechanism

is the reaction of the catalyst with a hydroxyl- or epoxy-

terminated initiator to form the active species. The reaction

follows a coordination–insertion mechanism into the Ca–O bond,

as proven by the chain end groups (for instance, for entries 14

and 15, one hydroxyl group and one ester). The proposed

Scheme 9 ROP of e-CL catalysed by LDA.34

Scheme 10 ROP of e-CL catalysed by cyclopentadienyl sodium.36

Scheme 11 ROP of e-CL using bis(tetrahydrofuran)calcium bis[bis(trimethylsilyl)amide]–alcohol system, adapted from Zhong et al .43


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mechanism for the following steps is shown in Scheme 12.

Termination is achieved through the addition of an acid.

Tang et al.46 studied strontium-based systems: strontium

ammoniate isopropoxide (ESIw Table 1.2, entry 17), and

strontium di-isopropoxide (ESIw Table 1.2, entry 18). Both

systems led to high molecular weight polymers with a highpolydispersity, but the isopropoxide–amine complex resulted

in a significantly broader molecular weight distribution (PDI

up to 7.4 versus up to 3.3). The high PDI indicates considerable

transesterification. The reaction mechanism is the same as for

the calcium ammoniate catalysed reaction (Scheme 12), with

strontium instead of calcium, and R = – i Pr.

3. Poor metal-based catalysts. Most of the metal-based

compounds used to catalyse the ROP of e-CL belong to the poor

metals group, most commonly aluminium- or tin-based catalysts.

a Aluminium-based catalysts. Aluminium is a less active

catalyst than many other metals for the ROP of lactones butis widely used because it allows a good control over the

reaction.32 Wang and Kunioka studied different metal triflates,

including aluminium(III) triflate (ESIw Table 1.3, entry 1), for the

ROP of e-CL.47 All polymerisations were carried out under air at

60 1C without stirring. Aluminium(III) triflate was found to be the

best performing catalyst (M n = 18400 g mol1, PDI = 1.94),

followed by copper(II) triflate (M n = 16 4 00 g mol1,

PDI = 1.97, ESIw Table 1.3 entry 28). Sodium(I), magnesium(II)

and ytterbium(III) triflates did not catalyse the reaction while

lanthanum(III) and samarium(III) triflates produced only

oligomers (M n = 300 g mol1). Dubois et al.48 studied

the ROP of e-CL using a diethylaluminium alkoxide

(ESIw Table 1.3, entry 4), and a triethylaluminium–aminesystem (ESIw Table 1.3, entry 5). Using diethylaluminium

alkoxide, a,o-hydroxyl-PCL containing an amide group inside

the chain was obtained. This suggests that not only the

alkoxide but also the amino group initiate the polymerisation

reaction. With the triethylaluminium–amine system, an

a-hydroxy-o-N -n-butylamide PCL is formed. When the amine

and the catalyst are introduced in the same molar ratio, thesolution gels and the GPC chromatogram is bimodal, suggesting

the presence of two different active sites. The initiation is

proposed to proceed through the nucleophilic attack of the

amine on the carbonyl group of the monomer (Scheme 13).

The monomer then opens through cleavage of the acyl–oxygen

bond, with ethane formation. The alkyl aluminium present at

the end of the chain is responsible for the propagation step

through insertion of the monomer into the O–Al bond. The

reaction is terminated by acid hydrolysis.

Florjan ´ czyk and co-workers used a methylaluminoxane–

trimethylaluminium system to catalyse–initiate the ROP of

e-CL.49 This system did not exhibit control over the poly-

merisation (PDI E 2) and back-biting reactions occurred,

leading to the formation of macrocycles. The reaction is said

to proceed through the insertion of the monomer into the

Al–O–Al bond, as shown in Scheme 14.

Duda et al.50 studied the synthesis of PCL using

different aluminium alkoxides, namely diethylaluminium

methoxide (ESIw Table 1.3, entry 6), diethylaluminium allyl-

oxide (ESIw Table 1.3, entry 7) and diisobutylaluminium

methoxide (ESIw Table 1.3, entry 8). Each molecule of

R2AlOR0 initiates one macromolecule, suggesting that only

alkoxy groups, and not alkyl groups are active in ROP. Like

other authors, Duda et al. noticed that the mechanism of

the reaction is pseudo-anionic with a propagation which isproposed to proceed through the cleavage of the acyl–oxygen

Scheme 12 Mechanism for the ROP of e-CL catalysed by calcium ammoniate.44

Scheme 13 Mechanism of the ROP of e-CL initiated by n-butylamine and catalysed by triethylaluminium.48


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bond of the monomer. Moreover, bulkier alkyl substituents on

the aluminium centre led to a more efficient polymerisation.

One of the most studied aluminium-based catalysts isaluminium(III) isopropoxide (ESIw Table 1.3, entry 9).33,37,51–60

It is known that in some solvents, aluminium isopropoxide

molecules do not exist as single molecules but as trimers

(A3) or tetramers (A4), which do not have the same

reactivity.52–54,58,59,61,62 An equilibrium exists between the

two species (Scheme 15), with the tetramer being more stable

than the trimer. Dissolved in e-CL, the A3 species disaggregate,

leading to a single species A1 (Scheme 16), which then form a

six-coordinated aluminium complex, [Al(Oi Pr)33e-CL],58,61,62

the actual catalyst–initiator for ROP of e-CL.61 When com-

mercial aluminium(III) isopropoxide is freshly distilled, it is

mainly composed of A3 species while A4 forms with time.61

The polymerisation rate of e-CL using the A1 species is far

higher than the interconversion rate between A3 and A4. As a

consequence, A3 leads to faster and more controlled poly-

merisations than A4.53

At complete conversion, the coordination number of

the aluminium centres has been proved to be either 4 or 6,

meaning that there is coordination between the ester groups of

the PCL and the aluminium centre (Scheme 17).53,58

Duda studied the effect of the presence of different alcohols

(poly(ethylene glycol), 1,5-pentanediol, propan-2-ol, ethanol).52

Alcohols act not only as a chain-transfer agent, but also

inhibit the polymerisation catalysed by aluminium isoprop-

oxide in its A3 form while they accelerate the polymerisation

catalysed by aluminium isopropoxide in its A4 form. As a

result, in the presence of alcohol, the polymerisation rate stays

the same, irrespective of the A3 : A4 ratio. The Al(Oi Pr)3

catalysed ROP of e-CL has also been shown to be more

controlled at lower temperature (0 to 25 1C in comparison

to B100 1C).64 A comparison of aluminium isopropoxide with

other metal alkoxides by Kricheldorf et al. showed activity

for all alkoxides (ESIw Table 1.3, entry 9a).55 However,

aluminium isopropoxide was found not to induce degradationof the polymer by intramolecular transesterification or back-

biting, unlike other metal alkoxides. Aluminium isopropoxide-

catalysed ROP of e-CL in scCO2 (ESIw Table 1.3, entry 8a)

was found to result in a large polydispersity (PDI = 2.3–4.3),

irrespective of the reaction conditions.37,51 This is believed to

be due to the formation of a large number of different species

with different reactivities when the aluminium alkoxide is

treated with CO2. In particular, alkoxide groups react with

carbon dioxide to give carbonates.51

Scheme 14 Mechanism of the initiation step of the ROP of e-CL initiated/catalysed by methylaluminoxane, adapted from Flojańczyk et al .49

Scheme 15 Equilibrium between A3 and A4 clusters of aluminium(III)

isopropoxide, adapted from Ropson et al .62,63

Scheme 16 Disaggregation of A3 species in e-CL, adapted from

Dubois et al .63

Scheme 17 Coordination between the ester groups of the polymer and the aluminium centre after complete conversion of the monomer, adapted

from Duda and Penczek.53


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Different methylaluminium diphenolate–alcohol systems

(ESIw Table 1.3, entries 17–19) resulted in PCL with controlled

molecular weight and low polydispersity indices.65 The

presence of an alcohol to initiate the reaction was necessary

as no polymerisation occurred with only methylaluminium

diphenolate (cf. ESIw). The actual initiating species is

an aluminium alcoholate formed by exchange between the

alcohol and one of the phenyl groups attached to the metal.

Bhaw-Luximon et al. polymerised e-CL in dichloromethane

using an aluminium Schiff base complex: HAPENAlOi Pr

(ESIw Table 1.3, entry 21), and in toluene using aluminium

isopropoxide (ESIw Table 1.3, entry 9a).33 The polymerisation

was complete after a few hours at 25 1C and a medium

molecular weight polymer was obtained (M n = 5700 g mol1).

The polymerisation occurs through a coordination–insertion

mechanism. Taden et al. polymerised e-CL using different

aluminium Schiff bases based on Salen (ESIw Table 1.3, entries

28 and 29) and Salcen (ESIw Table 1.3, entries 30 and 31)

ligands.66 Only limited information is given on the poly-

merisation conditions and on the resulting polymers.

However, it is said that the alkyl complexes oligomerise

e-CL while the chloro complexes (cf. ESIw) fail to initiate

ROP. Arbaoui et al. also used different aluminium Schiff bases

(ESIw Table 1.3, entries 22–27).67 These complexes exhibited a

good control of the reaction at low temperature (25 and

40 1C). At higher temperatures, however, control was lost.

At low catalyst concentration, not only one, but both of the

Al–alkyl bonds participated in the polymerisation process.

Different Al complexes based on salicylaldimines (ESIw

Table 1.3, entries 32–35) with different substituents on the

imino group, showed an increasing activity in the substituent

order C6F5 – 44 2,6-i PrC6H3 – 44 tert-butyl– 4 adamantyl–.

68

The effect of different substituents on the two phenyl rings of

the ligand (e.g. Me, i Pr, Ph, F, Cl, tBu) of salicylaldimine-

based aluminium Schiff bases (ESIw Table 1.3, entries 42–57)

has also been reported.69 A bulky substituent on the imine

moiety enhanced the polymerisation while bulky substituents

on the salicylidene moiety seem to slow it down. In particular,

among the different Schiff bases tested, the most efficient one

contained a 2,4,6-tri-tert-butylphenylimine moiety and a

methyl substituent on the 3-position of the salicylidene moiety,

which led to complete conversion of the monomer in a few

minutes (entry 53). Increasing the temperature was found

to speed up the reaction, but also slightly broadened the

molecular weight distribution. Moreover, when the reaction

is carried out in concentrated conditions, the polymerisation

rate is even more important.

Yao et al. used different aluminium Schiff bases based on

anilido-imine (ESIw Table 1.3, entries 36–41).70 The reactivity

decreased with increasing size of the substituents on the

two phenyl rings. It was postulated that it is easier for

the monomer to coordinate to the aluminium centre when

the ligand is less bulky. All tested complexes showed a high

catalytic activity when benzyl alcohol was used to initiate

the reaction, while no polymerisation occurred without

alcohol. In the first step of the reaction, the alcohol reacts

with the alkyl aluminium to form the active species. A

molecule of monomer will then coordinate to the metal centre.

The ring cleaves at the acyl–oxygen bond and is inserted into

the Al–O bond of the active species. The alcohol does not only

act as an initiator, but also as a transfer agent. Thus, a

polymeric chain can be de-activated or re-activated easily

throughout the polymerisation process.

Different (5,10,15,20-tetraphenylporphinato) (TPP) aluminium

alkoxide–alcohol systems (ESIw Table 1.3, entries 58–60) resulted

in PCL with different end groups depending on the system used.71

The polymerisation time is long: 220 h to 24 days for complete

conversion but occurs at relatively low temperature (room

temperature to 50 1C) and leads to a narrow molecular weight

distribution (around 1.1). The polymer chains appear to grow not

only from the TPP aluminium alkoxide introduced in the

medium, but also from the TPP aluminium alkoxide obtained

from the exchange between the starting TPP aluminium alkoxide

and the alcohol introduced in the medium (Scheme 18).

The exchange reactions are much faster than the propagation

reactions, leading to a narrow polydispersity.

Ko, Lin and co-workers investigated the polymerisation of

e-CL using various aluminium complexes (ESIw Table 1.3,

entries 61–67).72–74 Using 2,20-ethylidenebis(4,6-di-tert-butyl-

phenol) ([(EDBP)Al(m-OBn)]2 and [(PhCHO)Al(EDBP)-

(m-OBn)]2, (entries 61 and 62), the resulting polymer has a

high molecular weight (up to 44 000 g mol1) with a narrow

polydispersity (1.04 to 1.15).73 The structures of the

compounds are dimeric. During the initiation process, a molecule

of monomer coordinates to one of the aluminium centres of the

dimeric catalyst to form a pentacoordinated intermediate. Then,

a benzylalkoxy group attacks the lactone (Scheme 19). The

polymerisation is slower with the [(PhCHO)Al(EDBP)-

(m-OBn)]2 than with [(EDBP)Al(m-OBn)]2, which is believed to

be due to the presence of benzaldehyde that slows down the

coordination of the monomer with the aluminium centre.

A more sterically hindered complex, 2,20-methylenebis-

(4,6-di(1-methyl-1-phenylethyl)-phenol) ([(MMPEP)Al(m-OBn)]2,

ESIw Table 1.3, entry 67), expected to be more active, resulted

in high molecular weight polymers with narrow polydispersity

bearing a benzyl end chain.74 The initiation occurs through the

insertion of a benzyl alkoxy group from the catalyst to the

monomer, leading to the formation of an aluminium alkoxide

intermediate. Ko, Lin and co-workers then used aluminium

thiolate compounds (entries 63–66) to prepare high molecular

weight polymers with a thiolate chain end.72 The catalyst from

entry 63 led to a better controlled polymerisation than the

entry 64 catalyst, but no reason was given. The polymerisation

rates of catalysts in entries 65 and 66 are slower than the

polymerisation rates of catalysts from entries 63 and 64, due to

the single Al–S functionality in 65 and 66 and two Al–S

Scheme 18 ROP of e-CL using TPP aluminium alkoxide–alcohol

systems.71


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linkages in 63 and 64. In addition, the initiation is much slower

using the compounds from entry 66 than for the system in

entry 65, due to steric hindrance of the alkyl groups on the

aluminium. The initiation occurs through the insertion of athiolyl group from the catalyst into the monomer, forming an

aluminium alkoxide intermediate which then reacts with the

monomer.

Dagorne et al. synthesised a large number of amino-

phenolate aluminium-alkyl and -alkoxide compounds

(ESIw Table 1.3, entry 68) and investigated them to initiate/

catalyse the ROP of e-CL.76 With the aluminium alkyl

compounds, the monomer formed a complex but the ring

could not be opened under the applied reaction conditions.

With the aluminium alkoxide compounds, e-CL could be

easily opened, confirming other work.

b Tin-based catalysts. Stannous(II) ethylhexanoate (or tin

octoate), is certainly the catalyst which has been used most

often for the ROP of e-CL (ESIw Table 1.4, entry 1). It is

effective, commercially available, easy to handle and soluble in

the most commonly used organic solvents.77 It must be used

together with a nucleophilic compound (generally an alcohol)

to initiate the reaction if a controlled synthesis of the polymer

is to be obtained. The main drawback of tin octoate is that it

requires high temperature, which encourages intermolecular

and intramolecular esterification and thus broadens the

polydispersity.77

Bhaw-Luximon et al. polymerised e-CL in dioxane and

toluene at 110 1C using a stannous(II) ethylhexanoate–

ethanolamine system (Scheme 20, ESIw Table 1.4, entry 1b).33

In dioxane, the conversion reached only 40% after 42 h, resultingin a low molecular weight polymer. In toluene, the polymerisation

completion was reached after 21 h and a medium molecular

weight polymer was obtained (M n = 5700 g mol1). The first

step of the polymerisation occurs through a complexation of

ethanolamine with stannous(II) ethylhexanoate. Both groups

(alcohol and amine) can then initiate the polymerisation of e-CL.

The combination of various initiators with tin(II) octoate was

reported by Yagci and co-workers.78–80 Initiators studied are

2-(1H -naphto[1,2-e][1,3]oxazin-2-yl)-ethanol (ESIw Table 1.4,

entry 1c), 3-cyclohexene-1-methanol (ESIw Table 1.4, entry 1d),

2-hydroxy-1,2-(diphenylethanone) (ESIw Table 1.4, entry 1e),

2-hydroxy-2-methyl propan-1-one (ESIw Table 1.4, entry 1f)

and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl propan-1-one (ESIw Table 1.4, entry 1g). These initiators were specially

chosen for their ability to initiate other kinds of polymerisation,

such that the resulting functionalised PCLs can be used as

macroinitiators for other polymerisation techniques.

Kowalski et al. described the influence of reaction

conditions on the rate of polymerisation and were able to

prove that the polymerisation process is living.81,82 Their

observations showed that the concentration of the growing

species remains constant throughout the process, that adding

alcohol (in particular butanol, ESIw Table 1.4, entry 1h)

increases the number of active sites, resulting in a higher

Scheme 19 ROP of e-CL catalysed by [(EDBP)Al(m-OBn)]2.75

Scheme 21 Formation of the active species for the ROP of e-CL using tin(II) octoate as a catalyst.81

Scheme 20 ROP of e-CL using Sn(Oct)2 –ethanolamine system according to Bhaw-Luximon et al .33


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polymerisation rate, and that carboxylic acids (in particular

ethyl hexanoic acid) temporarily convert the growing species

into dormant molecules, resulting in a decrease in the

polymerisation rate.

Indeed, the first step of the polymerisation (Scheme 21)

consists of the production of the active species by reacting the

alcohol with the catalyst. The more alcohol is added, the more

the equilibrium is displaced towards the right and the more

active species are created. With increasing carboxylic acid

concentration, the equilibrium shifts to the left and less active

species are present in the medium. This equilibrium exists

throughout the polymerisation (Scheme 22).

The alcohol plays the role of initiator when it is introduced

in a level up to twice the amount of catalyst. When it is

introduced in excess, it also plays the role of a transfer agent.

When the reaction is carried out without an alcohol-

terminated initiator (ESIw Table 1.4, entry 1a), impurities

present in the tin(II) octoate catalyst (around 1.8 mol% of

OH groups after two consecutive distillations under high

vacuum) appear to play the role of initiator.81 However,

without the addition of a nucleophilic compound, even if

polymerisation occurs, it is not controlled. Kowalski et al.

also showed, using MALDI-TOF analysis, that several species

were produced during polymerisation with two compounds

preferentially formed (Fig. 2).83,84 To explain the preferential

formation of these two main compounds, they postulated

that the catalyst is first transformed into an alkoxide in order

to be able to initiate the polymerisation. Subsequently, the

polymeric chain will grow by insertion of the monomer into

the alkoxide bond (Scheme 23). Moreover, the amount of

each fraction present in the medium depends on different

parameters, such as the concentration of initiator and the

polymerisation time.84

Tin(II) octoate has also been combined with ureido-

pyrimidinone-alcohol (UPy) compounds (ESIw Table 1.4, entries

1j and 1k) as initiators.85 The first alcohol compound, bearing

a methyl group, was not a good initiator due to its poor

solubility in organic solvents. Using the second more soluble

alcohol, bearing a 1-ethylpentyl moiety, the polymerisation

was significantly more controlled: near complete conversion

was reached and polymers with a medium polydispersity were

obtained (PDI = 1.1 to 1.36). However, it was mentioned that

dimerisation of the initiator occurred, potentially increasing

the measured polydispersity. Indeed, at the reaction temperature

(80 1C), there is a high rate of on/off UPy dimerisation (i.e. two

initiators can easily be associated by quadruple hydrogen

bonding (Scheme 24)). The dimer form does not interact

with the catalyst and formation of the polymeric chains is

postponed until the initiator is present in its monomeric form.

Bratton et al. investigated the polymerisation of e-CL

initiated by butan-1-ol and catalysed by stannous(II)

ethylhexanoate in scCO2 (ESIw Table 1.4, entry 1h).86 It

was found that increasing the pressure of the medium resulted

in a decrease in the polymerisation rate while increasing

the temperature increased the polymerisation rate. The

polymerisation in scCO2 was also compared to the same

Scheme 22 Formation of a dormant chain during the polymerisation of e-CL catalysed by tin octoate.81

Scheme 23 Initiation steps of the ROP of e-CL initiated by an alcohol and catalysed by tin(II) octoate according to Kowalski et al .83

Fig. 2 The different polymers formed during the ROP of e-CL initiated with butanol and catalysed with tin( II) octoate, the framed compounds are

preferentially formed.83


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polymerisation with the same conditions in organic solvents

and in bulk. It was found that the polymerisation rate in

scCO2 was the same as in THF, which was slightly slower

than in toluene and significantly slower than in bulk.

Primary amine–tin(II) octoate systems follow a similar reaction

mechanism as alcohol–tin(II) octoate systems. Two polyamino

dendrimers, DAB-Am-8 and DAB-Am-32 (ESIw Table 1.4,

entries 1n–1p), used as initiators resulted in high molecular

weight PCL dendrimers.87

Stassin et al. polymerised e-CL using dibutyltin dimethoxide

in scCO2 and compared it to the polymerisation in bulk, in

toluene and in 1,1,2-trichloro-1,2,2-trifluoroethane (CFC-113)

(ESIw Table 1.4, entry 3).88,89 The highest polymerisation rate

is obtained in bulk, then in toluene, followed by CFC-113,

while the polymerisation in scCO2 is the slowest.88 They

demonstrated that the alkoxide is carbonated in scCO2,

slowing down the reaction as discussed before.89

The efficiency of tin triflate (ESIw Table 1.4, entry 6) and

scandium triflate (ESIw Table 1.4, entry 1) for the ROP of

e-CL has been compared with tin octoate (ESIw Table 1.4,

entry 1m) and (Bu)2Sn(Oct)2 (ESIw Table 1.4, entry 4).77,90

The living character of the polymerisation is proven by the

linear relationship between molecular weight and conversion.

At 110 1C, the temperature which gives the best results with tin

octoate, the polymers obtained with the triflate compounds

showed a similar molecular weight and polydispersity to these

obtained with Sn(Oct)2 and (Bu)2Sn(Oct)2, but with a reduced

reaction time (3 h instead of 24 h). At low temperatures,

triflate compounds led to high molecular weight polymers with

narrow polydispersity while there was no conversion of the

monomer with the two other catalysts. The polymerisation

of e-CL by tin triflate is proposed to proceed through a

coordination–insertion mechanism.

4. Transition metal-based catalysts. If we exclude scandium,

yttrium and lanthanum (see section 5. Rare earth metal-based

catalysts), the most commonly used transition metal for the ROP

of lactones is titanium, but recently, zirconium has attracted

some interest.32 In general, the less toxic metals are used

preferentially.

Zinc mono- and di-alkoxides have been reported to be good

initiators for the ROP of e-CL (ESIw Table 1.5, entries 31–34),

resulting in a degree of polymerisation (DP) over 100

being obtained with a PDI between 1.05 and 1.1.91 The poly-

merisation is carried out through a coordination–insertion

mechanism relying on the cleavage of the acyl–oxygen bond

of e-CL (Scheme 25).

Sarazin et al. used different zinc complexes (ESIw Table 1.5,

entries 36 and 37) and reported them to be more stable and

to show higher activity than their magnesium analogues.92

Both complexes were found to be very good catalysts as the

polymers can be obtained with a high throughput (between 50

and 300 kg (mol metal)1 h1). No indication is given regarding

the molecular weight and polydispersity of the polymer

obtained with the first complex, but the one obtained

with the second complex presents a high molecular weight

(55000 g mol1) despite a moderate PDI (2.3).

Zinc oxide successfully catalysed the ROP of e-CL in the

presence of an ionic liquid ([bmim][BF4]) under microwave

treatment (ESIw Table 1.5, entry 29).93 The combination of

these two elements (ionic liquid + microwave) increases the

efficiency of the ROP. Polymers with average molecular

weights between 2260 g mol1 and 11060 g mol1 were

obtained with PDIs between 1.30 and 2.50. The reaction

mechanism of zirconium(IV) acetylacetonate catalysed ROP

of e-CL (ESIw Table 1.5, entry 39) has been elucidated by

Dobrzynski (Scheme 26).94

Scheme 24 Dimerisation of the ureidopyrimidinone-alcohol compound.

Scheme 25 ROP of e-CL using zinc mono-alkoxide.91

Scheme 26 ROP of e-CL using Zr(acac)4 according to Dobrzynski.94


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Iron(III) alkoxide complexes (ESIw Table 1.5, entries 26 and 27)

have been found to be efficient catalysts that led to high

molecular weight polymers.95 A narrow molecular weight

distribution was obtained with the di-Fe complex, but a

wider distribution was obtained with the mono-Fe complex.

This is said to be due to a low level of impurities which

deactivate the catalyst. For the polymerisation catalysed by

the di-Fe complex, the reaction is first order in both the

monomer and the complex. For the mono-Fe complex

catalyst, the polymerisation reaction is first order in the

monomer and depends on the square root of the complex

concentration.

Davidson et al. reported the use of titanium complexes

based on catechol ligands (ESIw Table 1.5, entries 6–13).96

All polymers synthesised presented a narrow polydispersity

suggesting controlled polymerisation. Chmura, Davidson and

co-workers investigated the use of titanium(IV) (ESIw Table 1.5,

entries 2–5) as well as zirconium(IV) (ESIw Table 1.5, entries

40–42) complexes with amine bis(phenolate) ligands.97,98 Only

the bulkiest titanium(IV) complex was found to be active.

However, the high polydispersity resulting from significant

transesterification reactions suggests that the polymerisation

was not controlled. As far as zirconium(IV) complexes were

concerned, the less bulky were more active and exhibited

better control over the polymerisation reaction. Also, minor

differences in the environment of the metal centre were

found to have a significant impact on the complex reactivity.

For both studies, polymers bearing isopropoxyl end chains

suggested that the initiation of the polymerisation occurs

via the isopropoxide groups of the complexes. Titanium(IV)

complexes with bisphenolate ligands (ESIw Table 1.5,

entry 15 and Table 2.4, entry 6) have been reported by

Takeuchi et al .99 The Lewis acidity of the catalyst

should not be too high for the polymerisation to occur.

Moreover, when polymerisation does occur, two polymer

molecules are formed for each molecule of catalyst present

(Scheme 27).

Mahha et al.100 investigated the oligomerisation of e-CL

using heteropolyacids (ESIw Table 1.5, entries 46–48 and 51),

molybdenum(VI) complexes (ESIw Table 1.5, entry 62 and

Table 2.4, entry 19), vanadium(IV) complexes (ESIw Table 1.5,

entry 25) and compared their activity to the activity of

sulfuric (ESIw Table 1.5, entry 16) and phosphoric (ESIw

Table 1.5, entry 17) acids. The reactions catalysed by hetero-

polyacids were found to work better under dioxygen than

under inert atmosphere. During the polymerisation under

inert atmosphere, V(IV) and Mo(V) species were reduced

and became inactive. Moreover, the polymerisation rate

with heteropolyacids was higher than with sulfuric and

phosphoric acids.

5. Rare earth metal-based catalysts. Rare earth metal-

based compounds are good catalysts due to their moderate

acidity.32 Moreover, these compounds do not have any known

toxicity.38 Scandium triflates (ESIw Table 1.6, entries 1a, 1c

and 1d) were combined with water and benzyl alcohol

(initiators) to catalyse the ROP of e-CL.101 High molecular

weight polymers (M n up to 25000 g mol1) with low poly-

dispersity index (PDI o 1.18) were obtained. Mo ¨ ller et al.

confirmed these results using ethanol, butan-2-ol and phenyl-

ethan-1-ol as initiators (ESIw Table 1.6, entries 1e–1g).77 Other

rare earth metal triflates, namely yttrium(III) (ESIw Table 1.6,

entry 3), lanthanum(III) (ESIw Table 1.6, entry 14), caesium(IV)

(ESIw Table 1.6, entry 17), neodymium(III) (ESIw Table 1.6,

entry 20), europium(III) (ESIw Table 1.6, entry 35), gadolinium(III)

(ESIw Table 1.6, entry 36), ytterbium(III) (ESIw Table 1.6,

entry 37) and lutetium(III) (ESIw Table 1.6, entry 39) triflates

where studied later using benzyl alcohol as initiator in both

organic solvents and ionic liquids.102 Scandium triflate was

the most efficient in toluene at 25 1C (M n = 3500 g mol1,

PDI = 1.13, total conversion in 2 h with [e-CL] : [Sc(OTf)3] :

[BnOH] = 50 : 1 : 1), slightly better than lanthanum triflate

(M n = 2900 g mol1, PDI = 1.16, complete conversion in 3 h,

same conditions). Various new initiators were also used. In

particular p-xylene glycol gave a polymeric chain which grew

from both hydroxyl groups, leading to two polymer chains

linked by p-xylene glycol. The signal obtained from GPC was

bimodal, probably due to the presence of water (from

the catalyst) which initiated other chains, leading to an

a-(carboxylic acid)-o-hydroxyl PCL. For the polymerisations

in ionic liquids, no initiator was added, but some water is

coordinated to the metal triflates. Three different ionic liquids

were tested: [bmim][BF4], [bmim][PF6] and [bmim][SbF6].

In [bmim][BF4], scandium and europium triflates did not

polymerise caprolactones and other rare earth triflates only

led to oligomers (maximum M n = 600 g mol1), while several

days were necessary to achieve a conversion of only 30%.

In [bmim][PF6], most of the polymerisation reactions were

complete after ca. 2 days and the resulting polymers had a

molecular weight of around 3000 g mol1. Lanthanum,

caesium, gadolinium and lutetium triflates led to longer

polymers (up to 4400 g mol1 for Lu(OTf)3). However,

the polymerisation did not appear to be controlled fully as

suggested by the polydispersity (PDI between 1.41 and 1.56).

In [bmim][SbF6], the molecular weights were lower than the

values obtained in [bmim][PF6], but polydispersities were

narrower. Moreover, when scandium, europium, gadolinium

and lutetium were used, it was impossible to separate the

polymer from the ionic liquid. The Ce(OTf)4 in [bmim][SbF6]

system was tested as a recyclable system for the ROP of

e-CL: it was possible to re-use it 3 times without any change

Scheme 27 Formation of 2 polymeric chains for 1 molecule of catalyst during the ROP of e-CL using a titanium(IV) complex.99


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in molecular weight and polydispersity of the polymer. The

mechanism of the reaction is cationic and monomer activated

(Scheme 28): first the monomer is coordinated to the catalyst to

form a complex, which is then attacked by the alcohol, thereby

freeing a proton that subsequently opens the ring to produce the

linear ester. The linear ester, playing the role of the alcohol,

repeats the same steps, leading to the polymer chain.

Deng and co-workers studied the ROP of e-CL catalysed

by yttrium(III) isopropoxide (ESIw Table 1.6, entry 4a) and

bimetallic isopropoxides containing yttrium (ESIw Table 1.6,

entries 5–7).103 Y(Oi Pr)3 (entry 4a) and Sn[Y(Oi Pr)4]2 (entry 7)

were revealed to be more efficient catalysts than Y[Al(O i Pr)4]3(entry 5) and Y[Sn(Oi Pr)3]3 (entry 6). In the two first

compounds, yttrium, the more active catalysing metal (Y–O

bonds have a greater activity than Sn–O or Al–O bonds), is

located towards the outside of the complex. The mechanism of

the reaction is said to be the same as for other alkoxides.

However, according to other authors, the mechanism of the

reaction with yttrium(III) isopropoxide is not as simple and it is

still unknown because the catalytically active compound is

actually a cluster of five yttrium atoms attached to a single

central oxygen atom.104,105

Rare earth metal phenyl compounds, namely triphenyl

yttrium (ESIw Table 1.6, entry 9), triphenyl neodymium (ESIw

Table 1.6, entry 19) and triphenyl samarium (ESIw Table 1.6,

entry 22) have been investigated for both bulk and solution

polymerisation (in toluene, THF, benzene and 1,4-dioxane).35

A higher molecular weight and yield were obtained for

polymerisation in bulk, while only oligomers were obtained

when it was conducted in THF or 1,4-dioxane. These systems

were found to be more efficient than phenyl lithium. However,

rare earth metal phenyl compounds not only catalyse the

polymerisation of PCL but also its decomposition. Consequently,

the polymerisation reaction needs to be stopped early enough

to prevent the decomposition of the formed polymer. It was

suggested that neither the acyl–oxygen bond nor the alkyl–

oxygen bond is cleaved during the initiation. Instead, the

polymerisation is said to follow a coordination–deprotonation–

insertion process (Scheme 29), followed by an intramolecular

transesterification in the later stage when decomposition of the

polymer starts.

Agarwal et al. used tris(bis-trimethylsilyl)amido samarium

(ESIw Table 1.6, entry 24) and samarium trihalide complexes

Scheme 28 Monomer-activated cationic mechanism for the ROP of e-CL initiated by scandium triflate.

Scheme 29 ROP of e-CL using rare earth phenyl compounds according

to Deng et al .35


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(ESIw Table 1.6, entries 25 and 26).106 These compounds were

found to be good catalysts for room temperature ROP

of e-CL. They give high molecular weight polymers

(M n 4 10 000 g mol1) over a short period of time (only a

few minutes) with a high monomer conversion (498%). The

reaction is also found to be more efficient at low temperature

(10 1C) than at room temperature. However, these catalysts

give rise to a relatively high polydispersity index of the final

polymer (B2.0). The first reaction step is likely to be the

decoordination of THF in exchange for an e-CL molecule.

Several kinds of initiating species are then produced

(Scheme 30).

Yttrium isopropoxide grafted onto silica surfaces (ESIw

Table 1.6, entry 8) was used in toluene at 40 1C in the presence

of 2-propanol.56 This heterogeneous system led to moderate

molecular weight polymers (M n B 1900 g mol1) in a short

time (B1 h). However, some silica particles can easily remain

attached to the polymeric chains if no particular care is taken

when detaching the polymeric chains from the support. After

treatment with a termination agent (aqueous hydrochloric

acid solution or alcohol), the silica particles must be allowed

to settle down for several hours before the supernatant can be

analysed. The propagation of the polymerisation mechanism is

based on a fast alkoxide–alcohol exchange leading to a

low polydispersity index (Scheme 31). The catalyst is easily

regenerated if the termination agent is 2-propanol.

Lin et al. polymerised e-CL using a lanthanum complex

based on a Schiff base ligand (ESIw Table 1.6, entry 16) and

obtained high molecular weight polymers with a unimodal

molecular weight distribution.107 Only one species was found

to be active and the polymerisation was said to proceed

through acyl–oxygen bond cleavage.

Samarium(II) aryloxide complexes (ESIw Table 1.6, entries

27 and 28) resulted in high molecular weight polymers with a

narrow polydispersity within a few minutes and at room

temperature.108 At the early stage of the polymerisation, a

colour change from dark brown to pale yellow proved that

Sm(II) was immediately oxidised to Sm(III), suggesting that

Sm(III) actually catalyses the reaction. The termination step

involved the addition of an alcohol, which forms an alkoxide

at the end of the polymeric chain (Scheme 32). However,

because of paramagnetism of samarium species, no information

is available on the structure of the growing species before

termination. As a consequence, the mechanism of the reaction

is still unknown.

Various organolanthanide complexes have also been studied

as catalysts: SmMe(C5Me5)2(THF) (ESIw Table 1.6, entry 29),

Scheme 30 ROP of e-CL using Sm(III) m-bromo-bis(trimethylsilyl)amido complexes according to Agarwal et al .106

Scheme 31 ROP of e-CL with yttrium isopropoxide grafted onto silica surfaces.56

Scheme 32 Formation of an alkoxide at the end of the polymeric

chain when an alcohol is used to terminate the polymerisation.108


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[SmH(C5Me5)2]2 (ESIw Table 1.6, entry 30), [YbMe(C5H5)2]2(ESIw Table 1.6, entry 38), SmOEt(C5Me5)2(Et2O) (ESIw

Table 1.6, entry 31), [YOMe(C5H5)2]2 (ESIw Table 1.6, entry 10)

and YOMe(C5Me5)2(THF) (ESIw Table 1.6, entry 11).109

The polymerisation gave high molecular weight polymers

(M n up to 140000 g mol1) with a narrow polydispersity

(1.05 to 1.19). The mechanism of the reaction was determined

to be different for each catalyst. The reaction of

[SmH(C5Me5)2]2 with e-CL produced 1,6-hexanediol after

hydrolysis, indicating a reduction of the carbonyl group of

the monomer (Scheme 33).

The reaction of SmMe(C5Me5)2(THF) with e-CL produced

7-hydroxy-2-heptanone after hydrolysis, indicating a scission

of the acyl bond followed by an alkyl addition (Scheme 34).

The reaction of SmOEt(C5Me5)2(Et2O) with e-CL produced

5-(ethoxycarbonyl)pentyl acetate after hydrolysis. The structure

obtained was the same as Endo et al.71 obtained when using

(5,10,15,20-TPP) aluminium ethyl, indicating that a similar

mechanism occurred here (Scheme 35).

The reaction of YOMe(C5Me5)2(THF) with e-CL does not

occur if the two compounds are introduced in stoichiometric

quantities, resulting in the recovery of the monomer upon

hydrolysis. For the reaction to occur, twice the amount of

monomer must be used. In this case, an ester alcohol is

produced and 1 equivalent of monomer remains unreacted

(Scheme 36).

Martin et al.110,111 reported on the polymerisation of e-CL

using [tris(hexamethyldisilyl)amide]yttrium in the presence of

2-propanol (ESIw Table 1.6, entry 12b). The alcohol was

required to control the polymerisation (PDI = 3.21 without

alcohol, ESIw Table 1.6, entry 12a). When used in the presence

of alcohol, the polymerisation using the yttrium amide was

well controlled up to an alcohol : yttrium ratio of 50 : 1. The

polymerisation progresses through the coordination–insertion

mechanism generally accepted for aluminium33,55 and yttrium103

alkoxides. First, yttrium alkoxide is formed by replacement of

the amide with the alcohol (Scheme 37). Propagation occurs

through insertion of the monomer into the Y–O bond by

Scheme 33 Reaction of e-CL with [SmH(C5Me5)2]2, followed by hydrolysis.109

Scheme 34 Reaction of e-CL with SmMe(C5Me5)2(THF), followed by hydrolysis.109

Scheme 35 Reaction of e-CL with SmOEt(C5Me5)2(Et2O), followed by reaction with acetic anhydride.109

Scheme 36 Reaction of e-CL with YOMet(C5Me5)2(THF) for different e-CL: catalyst ratios.109


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cleavage of the acyl bond of the monomer. The polymerisation

is stopped by the addition of an excess of acid. This produces

a polymeric chain with one hydroxyl chain end and one

isopropoxy ester chain end.

Using alcohols other than 2-propanol, namely methanol,

n-butanol, 1-phenyl-propan-2-ol, 2-(3-thienyl)ethanol and

N -pyrrol-2-ethanol, as initiator results in varying chain ends.

All gave rise to polymers with a controlled molecular weight

and a low polydispersity index.

An yttrium tris(2,6-di-tert-butylphenolate)–2-propanol system

(ESIw Table 1.6, entry 13) was used to produce PCL with a

controlled molecular weight and narrow polydispersity.104,112

The alcohol reacts with the catalyst to form yttrium iso-

propoxide. The reaction is thus virtually reduced to an yttrium

isopropoxide catalysed reaction. Indeed, the use of a small

alcohol as initiator is necessary as the catalyst alkoxides are

too big to allow a direct reaction.

Mingotaud et al. used yttrium and lanthanum iso-

propoxides to catalyse the ROP of e-CL in bulk, in toluene

and in scCO2 (ESIw Table 1.6, entry 15).37 In bulk, the

polymerisation was not controlled at all (PDI = 6.2–8),

certainly because the catalyst is insoluble in the monomer,

giving rise to a heterogeneous system. In toluene and in scCO2,

the results are similar for yttrium isopropoxide, but the

reaction is much slower in scCO2 than in toluene for

lanthanum isopropoxide. By varying temperature and

pressure in scCO2, the best results were obtained at 110 1C

at a pressure of 200 bar.51

Metal-based compounds are certainly the most widely

studied class of catalysts for ROP of e-CL. However, enzymes

and organic compounds are gaining in importance and are

discussed in the following sections.

Enzymatic ring-opening polymerisation (eROP)

A mechanism for eROP using lipases has been proposed by

several authors (Scheme 38): first, the lipase reacts with

the monomer to form a lipase-activated CL complex, then the

alcohol reacts with the complex.113–116 Modelling studies on the

eROP of e-CL have revealed that polymerisation, degradation

and enzyme deactivation all occur simultaneously.117

Dong et al. showed that the water content in the reaction

medium is extremely important and must be neither too high,

nor too low to have polymers with a high molecular weight

and a narrow polydispersity using the lipase PSL (from

Pseudomonas sp.).118 Also, they found that adding molecular

sieves into the medium resulted in good control of the water

Scheme 37 Formation of the active species in the ROP of e-CL with yttrium amide and propan-2-ol.110,111

Scheme 38 Mechanism of the eROP.113–116

Scheme 39 Mechanism of the eROP proposed by Dong et al .118


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content, and consequently the polymerisation. A new mechanism

for the polymerisation of e-CL using PSL was subsequently

proposed: ring-opening occurs in the early stage of the poly-

merisation, and linear condensation in the later stage

(Scheme 39). This mechanism is consistent with the sharp

decrease in the amount of water at the early stage of the

polymerisation and its increase at the later stage. The pH was

also found to be important (optimal at 7.2 for PSL).119 Indeed,

the pH affects the ionisation of the amino acid residues at the

active site of the lipase, which influences its ability to bind to

substrates.

Kobayashi and coworkers113,114,120–125 have produced a

vast array of work on enzymatic catalysis of ROP of lactones

and in particular e-CL. They tested a wide number of enzymes

from different origins: porcine pancreas (PPL, ESIw Table 1.7,

entry 1), Aspergillus niger (lipase A, ESIw Table 1.7, entry 2),

Candida cylindracea (now called Cylindracea rugosa, lipases B

and CC, ESIw Table 1.7, entries 3 and 4), C. antarctica (lipase

CA, ESIw Table 1.7, entry 7), Pseudomonas aeroginosa (lipase

PA, ESIw Table 1.7, entry 8), Pseudomonas cepacia (now

called Burkholderia cepacia126 lipase PS-30, ESIw Table 1.7,

entry 9), Pseudomonas fluorescens (lipases P and PF, ESIw

Table 1.7, entries 10 and 11), Rhyzopus delemer (lipase RD,

ESIw Table 1.7, entry 14), Rhizopus japonicus (lipase RJ,

ESIw Table 1.7, entry 15) and hog liver esterase (HLE, ESIw

Table 1.7, entry 19).

A large number of different solvents were tested (1,4-dioxane,

acetonitrile, acetone, 2-butanone, tert-butyl alcohol, tert-butyl

methyl ether, isopropyl ether, benzene, carbon tetrachloride,

heptane, cyclooctane, and isooctane) and it appeared that the

efficiency of the polymerisation was linked to the hydro-

phobicity of the solvent used: when eROP was conducted in

hydrophilic solvents, the conversion was very low after 10 days

and the resulting polymers had a low molecular weight. It was

found that hydrocarbons are more suitable solvents for

eROP, while bulk reactions are still faster than reactions

in solution.123 The lipase CA was the most efficient: high

conversion was obtained in less than 24 h while more than

10 days were needed for the other lipases. In addition, a

smaller amount of enzyme was added to the reaction medium

(1–20 mg vs. 50 mg for 1 mmol of monomer). This is because

this particular lipase (Novozyms 435) was immobilised while

all the other lipases tested were used as a free powder. Kumar

and Gross confirmed many of their conclusions concerning the

use of hydrophilic or hydrophobic solvents for the Novozyms

435 lipase.127 They also showed that performing the reaction

on a larger scale increased the molecular weight of the poly-

mer: it is believed to be due to the susceptibility to take up

water during the reaction. Moreover, at higher dilution, the

PDI was found to be lower. A study on the influence of both

enzyme water content and polymerisation temperature on the

eROP of e-CL catalysed by Novozyms 435 showed that the

polymerisation temperature had little influence on the poly-

merisation.128 It was also noticed that a decrease in enzyme

water content increased the number of polymeric chains and

the average molecular weight of the polymer, consistent with

the fact that water is the actual initiator of the polymerisation.

Uyama et al. used lipase from C. antarctica (CA, ESIw

Table 1.7, entry 7a) and showed that the presence of an

initiator leads to a faster polymerisation reaction (78% of

conversion when [1-octanol]0/[e-CL]0 = 0.2 after 1 h of

reaction instead of 46% without alcohol).122 However, alcohol

addition led to shorter polymeric chains (M n = 1000 g mol1

instead of 5200 g mol1 with a conversion around 75%) with a

narrower distribution (PDI = 1.5 instead of 3.2), showing that

the presence of alcohol provides control over the polymerisation

reaction. Studies with Lipase B from C. antarctica (CALB,

Novozyms 435) and a lipase from P. cepacia (PC) showed

that the polymerisation is faster in bulk than in organic solvent

and shifted towards the formation of linear polymers, while

the reaction in acetonitrile, THF or dioxane tended towards

the formation of cyclic oligomers.129,130 Cyclic oligomer

formation is also enhanced in a more dilute system. For the

lipase from PC, the products are essentially linear, even in

solution.130 When CALB was used as a catalyst, the initial step

of the polymerisation involved nucleophilic attack of serine

105 of the lipase on the monomer.129,130 When a-D-gluco-

pyranoside and b-D-glucopyranoside were used as initiators,

CALB acylated the primary alcohol.130 Polymerisation of

e-CL with lipase from C. antarctica in scCO2 resulted in

polymers similar to those generally obtained with enzymes

in organic solvents, but with a narrower polydispersity.131

Hedfors et al. synthesised PCL terminated with thiol

functional groups using Novozyms 435 as a catalyst.132 This

was possible because this catalyst is chemoselective. Three

different methods were employed:

- the ROP was initiated by a compound with both alcohol

and thiol groups; the hydroxyl group initiated the reaction

while the thiol group remained unreacted;

- the ROP was initiated by the water present in commercial,

undried e-CL and was terminated by the addition of a

thiolactone: the lipase opens the thiolactone ring, the same

way it opens the lactone ring;

- the ROP was initiated by the water present in commercial,

undried e-CL and was terminated by the addition of a

compound bearing both carboxylic acid and thiol groups: a

transesterification reaction between the polymer and the

carboxylic acid group of the terminator gives the thiol-terminated

polymer.

The use of such chemoselective catalyst compounds for the

ROP of e-CL allows for a choice of the terminal groups on the

polymer without the need for any protecting and deprotecting

steps, a major advantage.

Porcine pancreatic lipase was tested under different conditions

by MacDonald et al. (ESIw Table 1.7, entries 1a and 1b).115

Different solvents (1,4-dioxane, toluene and heptane) were

tested and the best results were found for bulk reaction or

for reactions in heptane. The optimal temperature was 65 1C

for a reaction time of 96 h. Crude porcine pancreatic lipase

(PPL, ESIw Table 1.7, entry 1c) and P. cepacia lipase (PS-30,

ESIw Table 1.7, entry 9a) were investigated for bulk poly-

merisation of e-CL and resulted in crystalline polymers composed

of 12 to 25 units in 1100 h and 240 h, respectively.116 The

molecular weight distribution was not reported.

Ethyl glucopyranoside (EGP) was used as the initiator with

various enzymes, namely Candida rugosa (ESIw Table 1.7,

entry 4b), C. Antarctica (ESIw Table 1.7, entry 7g), P. fluorescens

(ESIw Table 1.7, entry 12), P. cepacia (ESIw Table 1.7,


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entry 9d), Mucor miehei (ESIw Table 1.7, entry 17), Mucor

javaniocus (ESIw Table 1.7, entry 18) and porcine pancreas

(ESIw Table 1.7, entry 1e) lipases.133 Only CA and PPL led to

significant monomer conversion. The structure of the resulting

polymer showed that the reaction was selective and that only

the primary alcohol was reactive. Surprisingly, under the same

conditions, methyl glucopyranoside (MGP) could not initiate

the reaction (cf. ESIw).

ROP catalysed by organic compounds and inorganic acids

Pratt and co-workers134,135 used aza-compounds, namely

1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, ESIw Table 1.8,

entry 1), N -methyl-1,5,7-triazabicyclo[4.4.0]dec-1-ene (MTBD,

ESIw Table 1.8, entry 2) and 1,8-diazabicyclo[5.4.0]-undec-7-ene

(DBU, ESIw Table 1.8, entry 3) as catalysts for the ROP of

e-CL. MTBU and DBU required co-catalysis by thiourea.

Indeed, thanks to its bifunctionality, TBD has the ability to

simultaneously activate both the alcohol and the monomer

(Scheme 40), while MTBD and DBU can only activate the

alcohol. The thiourea is needed to activate the monomer

(Scheme 41). The reaction is terminated by the addition of

benzyl alcohol: benzyl acetate is formed and the catalyst is

regenerated.

Phosphazene bases have been used to catalyse the poly-

merisation of e-CL, which was found to be well controlled

(predictable molecular weight, narrow PDI) but very slow

(only 14% conversion after 10 days at 80 1C).137 The proposed

mechanism is given in Scheme 42.

A study of various carboxylic acids (lactic acid, tartaric acid,

hexanoic acid, propionic acid, citric acid, 6-hydroxyhexanoic

acid, ESIw Table 1.8, entries 4–9) and amino acids (glycine,

proline and serine, ESIw Table 1.8, entries 10–12) in the

presence of benzyl alcohol to initiate the reaction have been

reported by Persson and co-workers.138,139 Organic acids with

pK a values between 3 and 5 were found to be able to catalyse

the ROP of e-CL, giving polymers with a weight average

molecular weight of up to 2800 g mol1 and a polydispersity

between 1.2 and 1.3. The order of catalytic efficiency is said to

be tartaric acid 4 citric acid 4 lactic acid 4 proline. The

other catalysts led to only a low conversion after 2–4 h

(o12%). The catalysts were recovered after precipitation of

the polymer in cold methanol, followed by filtration and

evaporation of the solvent under reduced pressure. The reaction

system could be reused up to two times without a decrease in

the molecular weight of the polymer. The ROP of e-CL with

these carboxylic acids and amino acids does not require

addition of an alcohol. In this case, the reaction is initiated

by an hydroxyl group or amine group present on the catalyst.

The polymerisation is proposed to proceed through a monomer

activation mechanism. In the initiation step, the nucleophile

(alcohol or amine) reacts with the proton-activated monomer.

The propagation occurs similarly, with the nucleophile being

the alcohol or amine-terminated chain.

Shibasaki et al. investigated the polymerisation of e-CL

catalysed by hydrochloric acid (in solution in diethyl ether)

and initiated with n-butanol.140 This is an inexpensive way to

produce polymers with narrow polydispersity. Methanesulfonic

Scheme 40 ROP of e-CL through dual activation using TBD, adapted from Chuma et al .136

Scheme 41 ROP of e-CL through dual activation using DBU and thiourea.134

Scheme 42 Mechanism for the ROP of e-CL using BEMP as catalyst.137


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acid (MSA) and trifluoromethanesulfonic acid (HOTf) were

compared with hydrochloric acid by Gazeau-Bureau et al .141

The ROP reaction is faster in toluene than in chlorinated

solvents. MSA was revealed to be as active as HOTf. The

activity of trifluoromethansulfonic acid is said to be optimal

for a catalyst : initiator ratio of 1 : 1 while the activity of MSA

increases with an increasing amount of catalyst, allowing a

faster reaction without a decrease in control. This is said to be

due to the competition between the activation of the monomer

and the deactivation of the alcohol (Scheme 43). Indeed, an

excess amount of HOTf would increase the deactivation of the

alcohol resulting in a slower polymerisation while an excess of MSA would increase the activation of the monomer, resulting

in a faster polymerisation.

Conclusion

The main route to obtain high molecular weight PCL is

the ROP of e-CL. A large number of compounds, either

metal-based, organic or even enzymatic systems can catalyse

the ROP of e-CL, as shown by the vast amount of published

work. Even some inorganic acids have been used successfully.

At present, metal-based compounds have been studied the

most, but enzymatic and organic compounds as well as

inorganic acids are gaining in prominence. Some catalysts

need specific conditions to catalyse the ROP of e-CL, while

several can be used in mild conditions. The termination step

usually requires the addition of an acid or of an alcohol, but

the polymer can also remain alive. The catalyst is mainly

chosen for the particular application, and the desired reaction

conditions.

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Scheme 43 Competition between the activation of the monomer and

the deactivation of the alcohol during the ROP of e-CL catalysed by

HOTf.


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