Synthesis of Pcl, A Review

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CRITICAL REVIEW

Synthesis of polycaprolactone: a revieww Marianne Labet and Wim Thielemans*

. 6 0 : 5 4 : 3 0 4 1 0 2 / 1 0 / 6 0 n o o i r a t n O n r e t s e W f o y t i s r e v i n U y b d e d a o l n w o D . 9 0 0 2 r e b m e t p e S 5 2 n o d e h s i l b u P

Received 15th January 2009 Received First published as an Advance Article on the web 25th September 2009 DOI: 10.103 10.1039/b820 9/b820162p 162p

Polycaprolactone (PCL) is an important polymer due to its mechanical properties, miscibility with a large range of other polymers and biodegradability. Two main pathways to produce polycaprolactone have been described in the literature: the polycondensation of a hydroxycarboxylic acid: 6-hydroxyhexanoic acid, and the ring-opening polymerisation (ROP) of a lactone: e -caprolactone ( e-CL). This critical review summarises the different conditions which have been described to synthesise PCL, and gives a broad overview of the different catalytic systems that were used (enzymatic, (enzymatic, organic and metal catalyst systems). systems). A surpri surprising sing variety of cataly catalytic tic systems have been studied, touching on virtually every section of the periodic table. A detailed list of reaction conditions and catalysts/initiators is given and reaction mechanisms are presented where known. Emphasis is put on the ROP pathway due to its prevalence in the literature and the superior super ior polymer that is obta obtained. ined. In addit addition, ion, ineffective ineffective system systemss that have been tried to cataly catalyse se the production of PCL are included in the electronic supplementary information for completeness (141 references).

Introduction Polycaprolactone (PCL) is an aliphatic polyester composed of hexanoate repeat units. It is a semicrystalline polymer with a degree of crystallinity which can reach 69%. 1 The unit cell is ˚ , orthorhombic and the lattice constants are a = 7.496  0.002 A ˚ and c = 17.297  ˚ , c being the b = 4.974  4.974  0.001 A 17.297  0.023 A

Driving Innovation in Chemistry and Chemical Engineering, School of Chemistry-Faculty of Science and Process and Environmental Environm ental Research Division-Faculty Division-Faculty of Engineer Engineering, ing, The University of Nottingham, University Park, NG7 2RD, United Kingdom. E-mail: [email protected] supplementary information (ESI) available: Tables of all w Electronic supplementary reaction systems and compound compounds. s. See DOI: 10.1039/b820162p 10.1039/b820162p

Marianne Marian ne Labe Labett was born in Angoule ˆ ˆ me, m e, France, France, in 198 1983. 3. She studied paper and printing eng ngin ineeer erin ing g at th thee Ec Ecol olee Franç aise de Papet Papeterie erie et des Industries Indust ries Graphi Graphiques, ques, INPG (Grenoble, France) from 2003 to 20 2006 06.. Sh Shee ob obta tain ined ed he herr Master Mas terss deg degree ree in mat materi erials als science in 2006 working under the supervision of Prof. Alain Dufresne and Dr W im Thiele Thi eleman mans. s. Sin Since ce 200 2006, 6, she has been a PhD student under thee su th supe perv rvis isio ion n of Dr Wi Wim m Marianne Labet Thielemans, at the University of Nottingham where she is working on the use of starch and cellul cel lulose ose nan nanocr ocryst ystals als as sub substr strate atess for the sur surfac facee init initiat iated ed ROP of lactones.

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fibre axis.2 The physical, thermal and mechanical properties of PCL depend on its molec molecular ular weight and its degre degreee of crysta crystalllinit lin ity. y. Ran Range gess of re repo port rted ed pr prop oper erty ty va valu lues es are sh show own n in Table 1. At room temperature, PCL is highly soluble in chloroform, dichloromet dichlo romethane, hane, carbo carbon n tetra tetrachlor chloride, ide, benze benzene, ne, tolue toluene, ne, cyclohexanone and 2-nitropropane; slightly soluble in acetone, 2-butanon 2-but anone, e, ethy ethyll aceta acetate, te, dimet dimethylfo hylformamid rmamidee and acet acetoonitrile nit rile;; and ins insolu oluble ble in alc alcoho ohols, ls, pet petrol roleum eum eth ether, er, die diethy thyll 7 ether and water water.. PCL dis displa plays ys the rare pro proper perty ty of bei being ng miscible with many other polymers (such as poly(vinyl chloride), poly(styrene–acrylonitrile), poly(acrylonitrile butadiene styrene), poly(bisph poly( bisphenolenol-A) A) and othe otherr polyc polycarbon arbonates, ates, nitro nitrocellul cellulose ose and cellu cellulose lose buty butyrate) rate),, and is also mecha mechanicall nically y co comp mpat atibl iblee

Wim Thi Thiele eleman manss obt obtain ained ed a Masters in Chemical Engineering in g fr from om th thee KU KULe Leuv uveen, Belgium in 1999 working under thee su th supe perv rvis isio ion n of Pr Prof of.. Ja Jan n Mewis and Prof. Jan Vermant. He re rece ceive ived d his PhD in 20 2004 04 work wo rkin ing g wi with th Pr Prof of.. Ri Rich char ard d Wool (Ch (Chemic emical al Eng Enginee ineering ring,, University of Delaware, USA). Wim subsequently moved to the INPG (Grenoble, France) as a postdoc post doctora torall res researc earcher/ her/Mari Mariee Curiee rese Curi research arch fel fellow low work working ing with Prof. Alain Alai n Dufresne Dufr esne and Wim Thielemans Prof. Pro f. M. Na Nace ceur ur Be Belga lgace cem. m. Since Sin ce Au Augus gustt 20 2006, 06, Wim has be been en a lec lectur turer er in che chemis mistr try y an and d chemical engineering at the University of Nottingham. His research interest inte restss incl include ude the surf surface ace modi modifica ficatio tion n of star starch ch and cel cellulo lulose se nanocrystals and their self-assembly. This journal is

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Table 1

Properties Propert ies of PCL

Properties

R a ng e

Ref.

Number average molecular weight (M n/g mol1) Density (r/g cm3) Glass transition temperature (T g/ C) Melting temperature temperature (T m/ C) Decomposition temperature (/ C) Inherent viscosity (Zinh/cm3 g1) Intrinsic viscosity (Z/cm3 g1) Tensile strength (s/MPa) Young modulus (E /GPa) Elongation at break (e/%)

530– 53 0–63 630000 0000

—

1 .0 7 1 – 1 .2 0 0 60 (65)–( 65)–( 60)) 5 6– 6 5 3 50 1 00–130 0 .9 4 –78 5 0 .2 1 – 0 .4 4 2 0–1000

1, 3 –6 3–5, 7 and 3–5, and 8 3–8 9 5 1 3 , 5 , 6 a nd 8 3 and 5 1, 3, 5, 6 and 8

1


1

1

with others (polye (polyethylene thylene,, polypro polypropylene pylene,, natura naturall rubber rubber,, poly(vinyl acetate), and poly(ethylene–propylene) rubber). PCL bio biodeg degrad rades es wit within hin sev severa erall mon months ths to sev severa erall yea years rs 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 degree of cry crysta stallin llinity ity whi while le the mol molecu ecular lar wei weight ght 9 remains constant. The Then, n, cle cleava avage ge of est ester er bon bonds ds res result ultss in mass loss.7,14 The pol polyme ymerr deg degrad rades es by end chain sci scissio ssion n at hig higher her tem temper peratu atures res whi while le it deg degrad rades es by ran random dom chain 13 scission scissio n at lower tempe temperatur ratures es (Fig. 1). PCL degra degradatio dation n is aut autoca ocatal talyse ysed d by the car carbox boxylic ylic aci acids ds lib libera erated ted dur during ing hydrolysis7 but it ca can n al also so be ca cata taly lyse sed d by en enzzym ymes es,, result res ulting ing in fas faster ter dec decomp omposi ositio tion. n. 11 Wh Whil ilee PC PCL L can be enzyma enz ymatic tically ally deg degrad raded ed in the env enviro ironme nment, nt, it can cannot not be 8 degraded enzymatically in the body.

Fig. 1

Scheme 1

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PCL has uses in different fields such as scaffolds in tissue engineering,9,14–16 in long-term drug delivery systems 7,10,11 (in particular contraceptives delivery 8), in microelectronics, 17 as adhesives,13 and in pac packag kaging ing.. 8 Its wid widee app applica licabil bility ity and interesting intere sting prop properties erties (con (controlle trolled d degra degradabili dability, ty, miscib miscibility ility with wit h oth other er pol polyme ymers, rs, bio biocom compat patibil ibility ity and pot potent ential ial 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 inexpensivel inexpensively. y. 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 catalytic sys system temss tha thatt hav havee bee been n stu studie died d to dri drive ve new deve de velo lopm pmen ents ts in ca cata talys lysis is (w (whe heth ther er or orga gani nicc-,, me meta tall- 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 polymer chemi chemists. sts. This review aims to be a ref refere erence nce work that can be use used d for this purpose 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-hydroxyhexanoic hexan oic acid are inter intermediar mediary y prod products. ucts. Industrially, Industrially, e-CL is produced from the oxidation of cyclohexanone by peracetic acid (Scheme 2). 19

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

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


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


Polymerisation There are two methods to prepare PCL: the condensation of 6-hydroxycaproic (6-hydroxyhexanoic) acid and the ringopening 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-hydroxyhexanoic 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 C. Polymerisation of 6-hydroxycaproic acid using lipase from Candida antarctica under vacuum gave rise to polymers with an average molecular weight of 9000 g mol 1 and a polydispersity under 1.5 in 2 days. 26 Using lipase from Pseudomonas sp. at 45 C to polymerise ethyl 6-hydroxyhexanoate resulted in polymers with an average molecular weight of 5400 g mol 1 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 1

1

Scheme 3

Scheme 4

Scheme 5

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 the formation of a cationic species which is attacked by the carbonyl oxygen of the monomer through a bimolecular nucleophilic substitution (S N2) 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

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

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

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

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Scheme 6


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

Scheme 7

Intermolecular transesterification reaction during the polymerisation of PCL.

Scheme 8

Intramolecular transesterification reaction during the polymerisation of PCL.

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 transesterification (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 all mentioned 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 metalbased 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 compound 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 recoil from 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 This journal is

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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, ESI w 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 C and a medium molecular weight polymer was obtained ( M n = 5700 g mol 1 when [e-CL]/[LDA] = 50). Phenyl lithium (ESI w Table 1.1, entry 2) led to high molecular weight polymers after a few hours at 170 C.35 Yuan et al.36 used cyclopentadienyl sodium (ESI w Table 1.1, entry 3) in bulk and in non-polar solvents to obtain number average molecular weights up to 130 000 g mol 1. 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. 1

1

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 (ESI w 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 (ESI w 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 mol1) with low to Chem. Soc. Rev., 2009, 38 , 3484–3504

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Scheme 9

Scheme 10

ROP of e -CL catalysed by LDA.34

ROP of e -CL catalysed by cyclopentadienyl sodium.36

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.

Scheme 11

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 epoxyterminated 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

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

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Scheme 12

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

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 (ESI w Table 1.2, entry 17), and strontium di-isopropoxide (ESI w Table 1.2, entry 18). Both systems led to high molecular weight polymers with a high polydispersity, 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 but is 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 C without stirring. Aluminium(III) triflate was found to be the best performing catalyst ( M n = 18400 g mol 1, PDI = 1.94), followed by copper(II) triflate (M n = 16 4 00 g mol1, 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 mol 1). Dubois et al.48 studied the ROP of e-CL using a diethylaluminium alkoxide (ESIw Table 1.3, entry 4), and a triethylaluminium–amine system (ESIw Table 1.3, entry 5). Using diethylaluminium 1

Scheme 13

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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, the solution 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 ćzyk 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 polymerisation (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 (ESI w Table 1.3, entry 6), diethylaluminium allyloxide (ESIw Table 1.3, entry 7) and diisobutylaluminium methoxide (ESIw Table 1.3, entry 8). Each molecule of R2AlOR 0 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 is proposed to proceed through the cleavage of the acyl–oxygen

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


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Scheme 14

Mechanism of the initiation step of the ROP of e -CL initiated/catalysed by methylaluminoxane , adapted from Flojanćzyk 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

the actual catalyst–initiator for ROP of e-CL.61 When commercial aluminium(III) isopropoxide is freshly distilled, it is mainly composed of A 3 species while A 4 forms with time. 61 The polymerisation rate of e-CL using the A 1 species is far higher than the interconversion rate between A 3 and A 4. As a consequence, A 3 leads to faster and more controlled polymerisations than A 4.53 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 isopropoxide in its A 3 form while they accelerate the polymerisation catalysed by aluminium isopropoxide in its A 4 form. As a result, in the presence of alcohol, the polymerisation rate stays the same, irrespective of the A 3 : 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 C in comparison to B100 C).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 degradation of the polymer by intramolecular transesterification or backbiting, unlike other metal alkoxides. Aluminium isopropoxidecatalysed ROP of e-CL in scCO 2 (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 1

1

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 is aluminium(III) isopropoxide (ESI w 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 (A 4), 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 A 1 (Scheme 16), which then form a six-coordinated aluminium complex, [Al(O i Pr)33e-CL],58,61,62

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: HAPENAlO i Pr (ESIw Table 1.3, entry 21), and in toluene using aluminium isopropoxide (ESI w Table 1.3, entry 9a). 33 The polymerisation was complete after a few hours at 25 C and a medium molecular weight polymer was obtained ( M n = 5700 g mol 1). The polymerisation occurs through a coordination–insertion mechanism. Taden et al. polymerised e-CL using different aluminium Schiff bases based on Salen (ESI w Table 1.3, entries 28 and 29) and Salcen (ESI w Table 1.3, entries 30 and 31) ligands.66 Only limited information is given on the polymerisation 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 C). 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 (ESI w 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 salicylaldiminebased aluminium Schiff bases (ESI w 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 (ESI w 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 1

1

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Scheme 18 ROP of e-CL using TPP aluminium alkoxide–alcohol systems.71

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 C) 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 2,2 0 -ethylidenebis(4,6-di-tert-butylphenol) ([(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 mol 1) 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, 2,2 0 -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 1

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Scheme 19

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

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 a thiolyl 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 aminophenolate 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 (ESI w 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 C using a stannous( II) ethylhexanoate– ethanolamine system (Scheme 20, ESI w Table 1.4, entry 1b).33 In dioxane, the conversion reached only 40% after 42 h, resulting in 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 mol 1). 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 (ESI w Table 1.4, entry 1c), 3-cyclohexene-1-methanol (ESI w Table 1.4, entry 1d), 2-hydroxy-1,2-(diphenylethanone) (ESI w Table 1.4, entry 1e), 2-hydroxy-2-methyl propan-1-one (ESI w Table 1.4, entry 1f) and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl propan1-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 1

Scheme 20

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

Scheme 21

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

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Scheme 22


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

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 alcoholterminated 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 ureidopyrimidinone-alcohol (UPy) compounds (ESI w 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 C), 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 1

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

Scheme 23

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


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Scheme 24

Dimerisation of the ureidopyrimidinone-alcohol compound.

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 (ESI w 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 scCO 2 is the slowest.88 They demonstrated that the alkoxide is carbonated in scCO 2, slowing down the reaction as discussed before. 89 The efficiency of tin triflate (ESI w 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 (ESI w 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 C, 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. 1

Scheme 25

Scheme 26

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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 polymerisation 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 (ESI w 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 h1). 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 mol1) despite a moderate PDI (2.3). Zinc oxide successfully catalysed the ROP of e-CL in the presence of an ionic liquid ([bmim][BF 4]) under microwave treatment (ESI w 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 mol1 and 11060 g mol 1 were obtained with PDIs between 1.30 and 2.50. The reaction mechanism of zirconium(IV) acetylacetonate catalysed ROP of e-CL (ESI w Table 1.5, entry 39) has been elucidated by Dobrzynski (Scheme 26). 94

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

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

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Iron(III) alkoxide complexes (ESI w 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 (ESI w 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 (ESI w 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 (ESI w Table 1.5, entries 46–48 and 51), molybdenum(VI) complexes (ESI w Table 1.5, entry 62 and Table 2.4, entry 19), vanadium( IV) complexes (ESI w Table 1.5, entry 25) and compared their activity to the activity of sulfuric (ESIw Table 1.5, entry 16) and phosphoric (ESI w Table 1.5, entry 17) acids. The reactions catalysed by heteropolyacids 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.

Scheme 27

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5. Rare earth metal-based catalysts. Rare earth metalbased compounds are good catalysts due to their moderate acidity.32 Moreover, these compounds do not have any known toxicity.38 Scandium triflates (ESI w 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 mol 1) with low polydispersity index (PDI o 1.18) were obtained. Mo ¨ ller et al. confirmed these results using ethanol, butan-2-ol and phenylethan-1-ol as initiators (ESI w 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) (ESI w 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 C (M n = 3500 g mol 1, 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 mol1, 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 mol 1), 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 mol 1. Lanthanum, caesium, gadolinium and lutetium triflates led to longer polymers (up to 4400 g mol 1 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][SbF 6] 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 1

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

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Scheme 28

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

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 (ESI w Table 1.6, entries 5–7).103 Y(Oi Pr)3 (entry 4a) and Sn[Y(O i 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(O i 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 (ESI w Table 1.6, entry 9), triphenyl neodymium (ESI w Table 1.6, entry 19) and triphenyl samarium (ESI w 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 3496 | Chem. Soc. Rev., 2009,

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Scheme 29 ROP of e-CL using rare earth phenyl compounds according to Deng et al .35

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 This journal is

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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

(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 mol1) 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 C) 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 (ESI w Table 1.6, entry 8) was used in toluene at 40 C in the presence of 2-propanol. 56 This heterogeneous system led to moderate molecular weight polymers ( M n B 1900 g mol 1) 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 (ESI w Table 1.6, entry 16) and 1

1

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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 (ESI w 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 32 Formation of an alkoxide at the end of the polymeric chain when an alcohol is used to terminate the polymerisation.108 Chem. Soc. Rev., 2009, 38 , 3484–3504

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Scheme 33

Scheme 34

Scheme 35

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

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

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

[SmH(C5Me5)2]2 (ESIw Table 1.6, entry 30), [YbMe(C 5H5)2]2 (ESIw Table 1.6, entry 38), SmOEt(C 5Me5)2(Et2O) (ESIw Table 1.6, entry 31), [YOMe(C5H5)2]2 (ESIw Table 1.6, entry 10) and YOMe(C5Me5)2(THF) (ESI w Table 1.6, entry 11).109 The polymerisation gave high molecular weight polymers (M n up to 140000 g mol 1) 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(C 5Me5)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(C 5Me5)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).

Scheme 36

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The reaction of YOMe(C 5Me5)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 aluminium 33,55 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

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

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Scheme 37

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

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 isopropoxide. 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 isopropoxides 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 scCO 2,

Scheme 38

Scheme 39

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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 scCO 2, the best results were obtained at 110 C 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. 1

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 118 Pseudomonas sp.). Also, they found that adding molecular sieves into the medium resulted in good control of the water

Mechanism of the eROP.113–116

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 polymerisation, 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, ESI w 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, ESI w 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, ESI w 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, ESI w 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 hydrophobicity 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 (Novozym s 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 Novozym s 435 lipase.127 They also showed that performing the reaction on a larger scale increased the molecular weight of the polymer: 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 Novozym s 435 showed that the polymerisation temperature had little influence on the polymerisation.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 3500 | Chem. Soc. Rev., 2009,

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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 mol 1 instead of 5200 g mol 1 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-glucopyranoside 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 Novozym s 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 C 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 polymerisation 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, 1

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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. ESI w).

ROP catalysed by organic compounds and inorganic acids

Pratt and co-workers 134,135 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 polymerisation 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 C).137 The proposed mechanism is given in Scheme 42. 1

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

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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 mol 1 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

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


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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.

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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