Synthesis of Polycaprolactone

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  • 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

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

    opening polymerisation (ROP) of  e-CL.


    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


    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–.


    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


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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


    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


    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


    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


    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

    3498   |   Chem. Soc. Rev.,   2009,   38, 3484–3504   This journal is  c   The Royal Society of Chemistry 2009

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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


    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


    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


    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.


    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



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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


    3502   |   Chem. Soc. Rev.,   2009,   38, 3484–3504   This journal is  c   The Royal Society of Chemistry 2009

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