Ringopening polymerization to polyesters

Various cyclic esters have been subjected to lipase-catalyzed ring-opening polymerization. Lipase catalyzed the ring-opening polymerization of 4- to 17-membered non-substituted lactones.16-18 In 1993, it was first demonstrated that medium-size lactones, 8-valerolactone (8-VL, six-membered) and e-caprolactone (e-CL, seven-membered), were polymerized by lipases derived from Candida cylindracea, Burkholderia cepacia (lipase BC), Pseudomonas fluorescens (lipase PF), and porcine pancreas (PPL).1920

P-Propiolactone (P-PL, 4-membered) was polymerized by Pseudomonas family lipases as catalyst in bulk, yielding a mixture of linear and cyclic oligomers with molecular weight of several hundreds,21 whereas poly(P-PL) of high molecular weight (molecular weight > 5 x 104) was obtained by using Candida rugosa lipase (lipase CR).22

Substituted four-membered lactones were polymerized via the lipase catalysis. The lipase-catalyzed polymerization of P-butyrolactone (P-BL) produced poly(P-hydroxybutyrate) (PHB),23 which is a polyester having similar structure produced in vivo by bacteria for an energy-storage substance. The molecular weight of PHB reached 7300 in the polymerization using PPL as catalyst at 100°C.24 Lipase CR also showed high catalytic activity toward the polymerization at high temperature. The resulting products contained a significant amount of cyclic oligo(P-hydroxybutyrate)s, which were formed by the lipase-catalyzed reaction of linear PHB.25

Poly(malic acid) is a biodegradable and bioadsorbable water-soluble polyester having a carboxylic acid in the side chain. The chemoenzymatic synthesis of poly(malic acid) was achieved by the lipase-catalyzed polymerization of benzyl P-malolactonate, followed by the debenzylation.26 The molecular weight of poly(benzyl P-malolactonate) increased on copolymerization with a small amount of P-PL using lipase CR catalyst.27

Five-membered unsubstituted lactone, 7-butyrolactone (7-BL), is not polymerized by conventional chemical catalysts. However, oligomer formation from 7-BL was observed by using PPL or Pseudomonas sp. lipase as catalyst.23 28 Enzymatic polymerization of six-membered lactones, 8-VL and 1,4-dioxan-2-one, was reported. 8-VL was polymerized by various lipases of different origins.19 29 The molecular weight of the enzymatically obtained polymer was relatively low (less than 2000).

In polyester synthesis via ring-opening polymerizations, metal catalysts are often used. For medical applications of polyesters, however, there has been concern about harmful effects of the metallic residues. Enzymatic synthesis of a metal-free polyester was demonstrated by the polymerization of 1,4-dioxan-2-one using Candida antarctica lipase (lipase CA).29 Under appropriate reaction conditions, the high molecular weight polymer (molecular weight = 4.1 x 104) was obtained.

e-CL (seven-membered lactone) is industrially manufactured and its oligomer having a hydroxy group at both ends is widely used as soft segment of polyurethanes. High molecular weight poly(e-CL) is a commercially available biodegradable plastic. So far, various commercially available lipases have catalyzed the e-CL polymerization. In the case of crude industrial lipases (PPL, lipases CR, BC, and PF), a large amount of catalyst (often more than 40 wt% for e-CL) was required for the efficient production of the polymer.3031 On the other hand, lipase CA showed high catalytic activity toward the e-CL polymerization; a very small amount of lipase CA (less than 1 wt% for e-CL) was enough to induce the polymerization.32 Under appropriate conditions, poly(e-CL) with the molecular weight close to 105 was obtained.33 34 During the polymerization of e-CL, degradation simultaneously took place.35 The polymerization in bulk produced the linear polymer, whereas the main product obtained in organic solvents was of cyclic structure, suggesting that intramolecular condensation took place during the polymerization. Recently, microwave-assisted lipase-catalyzed polymerization of e-CL was reported.36

In the polymerization of e-CL catalyzed by lipase CA in organic solvents, the polymer was obtained efficiently in solvents having log P (a parameter of hydrophobicity) values from 1.9 to 4.5, whereas solvents with log P from -1.1 to 0.5 showed low propagation rate.37 Among the solvents examined, toluene was the best solvent to produce high molecular weight poly(e-CL) efficiently. Variation in the ratio of toluene to e-CL in the reaction at 70°C showed that the monomer conversion and polymer molecular weight were the largest for a ratio about 2:1. Furthermore, lipase CA could be reused for the polymerization. In the range of five cycles, the catalytic activity hardly changed. The kinetics of the e-CL bulk polymerization by lipase CA showed linear relationships between the monomer conversion and the molecular weight of the polymer; however, the total number of the polymer chains was not constant during the polymerization.38 The monomer consumption apparently followed a first-order rate law.

Ring-opening polymerization of a-methyl-substituted medium-size lactones, a-methyl-8-valerolactone and a-methyl-e-caprolactone, proceeded by using lipase CA catalyst in bulk.39 Lipase CA efficiently catalyzed the ring-opening polymerization of 1,5-dioxepan-2-one.40 A linear relationship between the monomer conversion and the molecular weight of the polymer was observed. The monomer consumption followed a first-order rate law, suggesting no termination and chain-transfer reaction. The enzymatic polymerizability of 1,5-dioxepan-2-one was much larger than that of e-CL.

A nine-membered lactone, 8-octanolide (OL), was enzymatically polymerized.41 Lipases BC and CA showed high catalytic activity for the polymerization. Four unsubstituted macrolides, 11-undecanolide (12-membered, UDL),42 12-dodecanolide (13-membered, DDL),43 15-pentadecanolide (16-membered, PDL),44-46 and 16-hexadecanolide (17-membered),47 were enzymatically polymerized. Various lipases catalyzed the polymerization of these macrolides. For the polymerization of DDL, the activity order of the catalyst was lipase BC > lipase PF > lipase CR > PPL. The lipase CA-catalyzed polymerization of PDL proceeded fast in toluene to produce a high molecular weight polymer with the molecular weight higher than 8 x 104. Enzymatic ring-opening polymerization of macrolides (UDL, DDL, and PDL) proceeded even in an aqueous medium. The single crystals of the aliphatic polyesters enzymatically synthesized from these macrolides were prepared and their crystal structure was examined.48-50

Enzymatic synthesis of aliphatic polyesters was also achieved by the ring-opening polymerization of cyclic diesters. Lactide was not enzymatically polymerized under mild reaction conditions; however, poly(lactic acid) with the molecular weight higher than 1 x 104 was formed using lipase BC as catalyst at higher temperatures (80-130°C).51,52 Protease (proteinase K) also induced the polymerization; however, the catalytic activity was relatively low.

Scheme 2

Lipases CA, BC, and PF catalyzed the polymerization of ethylene dode-canoate and ethylene tridecanoate to give the corresponding polyesters.53 The enzyme origin affected the polymerization behaviors; in using lipase BC catalyst, these bislactones polymerized faster than e-CL and DDL, whereas the reactivity of these cyclic diesters was in the middle of e-CL and DDL in using lipase CA.

It is well known that the catalytic site of lipase is a serine residue and lipase-catalyzed reactions proceed via an acyl-enzyme intermediate. The enzymatic polymerization of lactones is explained by considering the following reactions as the principal reaction course (Scheme 2). The key step is the reaction of lactone with lipase involving the ring opening of the lactone to give an acyl-enzyme intermediate ("enzyme-activated monomer," EM). The initiation is a nucleophilic attack of water, which is contained partly in the enzyme, onto the acyl carbon of the intermediate to produce «-hydroxycarboxylic acid (n = 1), the shortest propagating species. In the propagation stage, the intermediate is nucleophilically attacked by the terminal hydroxyl group of a propagating polymer to produce a one-unit-more elongated polymer chain. The kinetics of the polymerization showed that the rate-determining step of the overall polymerization is the formation of the enzyme-activated monomer. Thus, the polymerization probably proceeds via an "activated-monomer mechanism."

Reactivity of cyclic compounds generally depends on their ring size; small and intermediate ring-size compounds possess higher ring-opening reactivity than macrocyclic lactones (macrolides) due to their larger ring strain. Table 2 summarizes dipole moment values and reactivities of lactones with different ring size. The dipole moment (indication of ring strain) of the macrolides is lower than that of 8-VL and e-CL and close to that of an acyclic fatty acid ester (butyl caproate). The rate constant of the macrolides in anionic polymerization is much smaller than

Table 2

Dipole moments and reactivities of unsubstituted lactones

Table 2

Dipole moments and reactivities of unsubstituted lactones

Ring size of lactones

Dipole moment (Cm)

Relative polymerization rate

Enzymatica

Chemicalb

6

4.42

2500

7

4.45

0.10

330

9

21

12

1.86

0.13

0.9

13

1.86

0.19

1.0

16

1.86

0.l4

0.9

17

1.00

1.0

Butyl caproate

1.15

a Calculated from Michaelis-Menten constants using lipase catalyst. b Polymerization with zinc octanoate/butyl alcohol initiator system in bulk.

a Calculated from Michaelis-Menten constants using lipase catalyst. b Polymerization with zinc octanoate/butyl alcohol initiator system in bulk.

that of 8-VL and e-CL. These data clearly show that the macrolides have much lower ring strain, and hence, show less anionic reactivity and polymerizability than the medium-size lactones.

On the other hand, the macrolides showed unusual enzymatic reactivity. Lipase PF-catalyzed polymerization of the macrolides proceeded much faster than that of e-CL. The lipase-catalyzed polymerizability of lactones was quantitatively evaluated by Michaelis-Menten kinetics. For all monomers, linearity was observed in the Hanes-Woolf plot, indicating that the polymerization followed MichaelisMenten kinetics. The Vmax(lactone) and Vmax(lactone)/Km(lactone) values increased with the ring size of lactone, whereas the Km(lactone) values scarcely changed. These data imply that the enzymatic polymerizability increased as a function of the ring size, and the large enzymatic polymerizability is governed mainly by the reaction rate (Vmax), but not to the binding abilities, i.e., the reaction process of the lipase-lactone complex to the acyl-enzyme intermediate is the key step of the polymerization.

Lipase catalyzed the ring-opening copolymerization of cyclic monomers. In 1993, the first example of the enzymatic ring-opening copolymerization of lactones was demonstrated; 8-VL and e-CL were copolymerized by lipase PF catalyst.54 The resulting copolymer was of random structure having both units. Random ester copolymers were also enzymatically synthesized from other combinations: e-CL-OL, e-CL-PDL, and OL-DDL. The formation of the random copolymers in spite of the different enzymatic polymerizabilities of these lactones suggests that the intermolecular transesterifications of the polyesters frequently took place during the copolymerization. By utilizing this specific lipase catalysis, random ester copolymers were synthesized by the lipase-catalyzed polymerization of macrolides in the presence of poly(e-CL).55

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