So far, various dicarboxylic acid derivatives, dicarboxylic acids, their activated and non-activated esters, cyclic acid anhydrides, and polyanhydrides have been polymerized with glycols through lipase catalysis to give polyesters.
Many diacids are commercially available; however, their enzymatic reactivity is relatively low. Therefore, the enzymatic polymerization of dicarboxylic acids and glycols was often carried out under vacuum for production of high molecular weight polyesters.56 57 In the Mucor miehei lipase (lipase MM)-catalyzed polymerization in hydrophobic solvents of high boiling points such as diphenyl ether and veratrole using a programmed vacuum profile, the molecular weight reached higher than 4 x 104. The increase of the molecular weight of aromatic polyesters was also observed by the polymerization under vacuum.58 In the polymerization of isophthalic acid and 1,6-hexanediol using lipase CA as catalyst at 70°C, the polyester with molecular weight of 5.5 x 104 was formed, whereas lipase MM only produced the corresponding oligomer.
The effects of substrates and solvents on the formation, molecular weight, and end-group structure of the polymer in the polycondensation using lipase CA as catalyst were systematically investigated.59 Diphenyl ether was found to be the preferred solvent that gave the polyester of the highest molecular weight. Concerning the effect of the monomer structure, the longer chain length diacids (sebacic and adipic acid) and diols (1,8-octanediol and 1,6-hexanediol) gave higher enzymatic reactivity than the shorter chain length of diacids (succinic and glutaric acid) and 1,4-butanediol.
Aliphatic polyesters were reported to be synthesized by enzymatic polymerization of dicarboxylic acids and glycols in a solvent-free system.6061 Lipase CA efficiently catalyzed the polymerization under mild reaction conditions, despite the heterogeneous mixture of the monomers and catalyst. Methylene chain length of the monomers greatly affected the polymer yield and molecular weight. The polymer with molecular weight higher than 1 x 104 was obtained by the reaction under reduced pressure. A small amount of adjuvant was effective for the polymer production when both monomers were solid at the reaction temperature.62 Scale-up experiment produced the polyester from adipic acid and 1,6-hexanediol in more than 200 kg yield.63 This solvent-free system claimed a large potential as an environmental-friendly synthetic process of polymeric materials owing to the mild reaction conditions and no use of organic solvents and toxic catalysts.
The polymerization of adipic acid and 1,8-octanediol in bulk was investigated by using lipase CA immobilized on different resins as well as lipase CA free of the immobilized resin.64 The immobilized lipase induced the polymerization more efficiently to produce the polyester of higher molecular weight. Under a wide range of reaction conditions, the molecular index of the resulting polymer without fractionation was less than 1.5, suggesting that lipase CA catalyzes the chain growth with chain length selectivity.
The effects of the feed ratio in the lipase CA-catalyzed polymerization of adipic acid and 1,6-hexanediol were examined by using NMR and MALDI-TOF mass spectroscopies.65 1H NMR analysis showed that the hydroxyl terminated product was preferentially formed at the early stage of the polymerization in the stoichiometric substrates. As the reaction proceeded, the carboxyl-terminated product was mainly formed. Even in the use of an excess of the dicarboxylic acid monomer, the hydroxy-terminated polymer was predominantly formed at the early reaction stage, which is a specific polymerization behavior due to the unique enzyme catalysis.
A dehydration reaction is generally realized in non-aqueous media. Since a product water of the dehydration is in equilibrium with starting materials, the solvent water disfavors the dehydration to proceed in an aqueous medium due to "the law of mass action." Nevertheless, the present authors have found that lipase catalysis provided a dehydration polymerization of a dicarboxylic acid and glycol in water.66 67 The view of dehydration in an aqueous medium is a new aspect in organic chemistry. Lipases BC, CA, CR, MM, and PF were active for the polymerization of sebacic acid and 1,8-octanediol. In the polymerization of a, w-dicarboxylic acid and glycol, the polymerization behavior greatly depended on the methylene chain length of the monomers. The polymer was obtained in good yields from 1,10-decanediol, whereas no polymer formation was observed using 1,6-hexanediol, suggesting that the combination of the monomers with appropriate hydrophobicity is favored for efficient polymer formation.
Alkyl esters often show low reactivity for lipase-catalyzed transesterifi-cations with alcohols. Therefore, it is difficult to obtain high molecular weight polyesters by lipase-catalyzed polycondensation of dialkyl esters with glycols. The molecular weight greatly improved by polymerization under vacuum to remove the formed alcohols, leading to a shift of equilibrium toward the product polymer; the polyester with molecular weight of 2 x 104 was obtained by the lipase MM-catalyzed polymerization of sebacic acid and 1,4-butanediol in diphenyl ether or veratrole under reduced pressure.68
Activated esters of halogenated alcohols, such as 2-chloroethanol, 2,2,2-trifluoroethanol, and 2,2,2-trichloroethanol, have been often used as substrate for enzymatic synthesis of esters, owing to an increase in the electrophilicity (reactivity) of the acyl carbonyl and avoid significant alcoholysis of the products by decreasing the nucleophilicity of the leaving alcohols.1
The enzymatic synthesis of polyesters from activated diesters was achieved under mild reaction conditions. The polymerization of bis(2,2,2-trichloroethyl) glutarate and 1,4-butanediol proceeded in the presence of PPL at room temperature in diethyl ether to produce the polyesters with molecular weight of 8.2 x 103.69 Vacuum was applied to shift the equilibrium forward by removal of the activated alcohol formed, leading to the production of high molecular weight polyesters.68 The polycondensation of bis(2,2,2-trifluoroethyl) sebacate and aliphatic diols took place using lipases BC, CR, MM, and PPL as catalyst in diphenyl ether. Under the appropriate reaction conditions, the polymer with molecular weight higher than 4 x 104 was obtained and lipase MM showed the highest catalytic activity.57 70 In the PPL-catalyzed polymerization of bis(2,2,2-trifluoroethyl) glutarate with 1,4-butanediol in 1,2-dimethoxybenzene, the periodical vacuum method increased the molecular weight to nearly 4 x 104.71
An irreversible procedure for the lipase-catalyzed acylation using vinyl esters as acylating agent has been developed, where a leaving group of vinyl alcohol tautomerizes to acetaldehyde. In these cases, the reaction with the vinyl esters proceeds much faster to produce the desired compounds in higher yields, in comparison with the alkyl esters.
Divinyl esters reported first by us are efficient monomers for polyester production under mild reaction conditions.72 In the lipase PF-catalyzed polymerization of divinyl adipate and 1,4-butanediol in diisopropyl ether at 45°C, a polyester with molecular weight of 6.7 x 103 was formed, whereas adipic acid and diethyl adipate did not afford the polymeric materials under similar reaction conditions (Scheme 3).
Lipase-catalyzed polymerization of divinyl ester and glycol is proposed to proceed as follows (Scheme 4). First, the hydroxy group of the serine residue nucleophilically attacks the acyl carbon of the divinyl ester monomer to produce an acyl-enzyme intermediate (EM) involving elimination of acetaldehyde. The reaction of EM with the glycol produces 1:1 adduct of both monomers. In the propagation stage, the nucleophilic attack of the terminal hydroxy group takes place on the acyl-enzyme intermediate formed from the vinyl ester group of the
O O Lipase PF
O O Lipase PF CH3CHzO-C—R—C-OCH2CH3 + HO—R'-OH -
Monomer conv,: quant. Polymer yield: 50% Molecular weight: 6700
Il II K
(Polymerization in /-propyl ether at 45°C for 48 h)
monomer and 1:1 adduct, and subsequently the propagation steps keep going similarly.
Lipases BC, CA, MM, and PF showed high catalytic activity toward the polymerization of divinyl adipate or divinyl sebacate with a, «-glycols with different chain lengths.73 A combination of divinyl adipate, 1,4-butanediol, and lipase PC afforded the polymer with molecular weight of 2.1 x 104. The yield of the polymer from divinyl sebacate was higher than that from divinyl adipate, whereas the opposite tendency was observed in the polymer molecular weight. The polyester formation was observed in various organic solvents, and among them, diisopropyl ether gave the best results.
During the lipase-catalyzed polymerization of divinyl esters and glycols, there was a competition between the enzymatic transesterification and the hydrolysis of the vinyl end group, resulting in the limitation of the polymer growth.74 A mathematical model showing the kinetics of the polymerization predicts the product composition (terminal structure).75 A comparison of the experimental data and model predictions suggests that the molecular weight and terminal group functionality of polyesters can be controlled by selection of biocatalysts. The reaction calorimetry was used to monitor the kinetics of the polymerization.76 The reaction rate increased as a function of the monomer concentration. As the polymerization proceeded, the rate constant for the polyester synthesis was significantly reduced. A batch-stirred reactor was developed to minimize temperature and mass-transfer effects.77 Using this reactor, poly(1,4-butylene adipate) with the molecular weight of 2.3 x 104 was synthesized in only 1 h at 60°C.
Aromatic polyesters were efficiently synthesized from aromatic diacid divinyl esters. Lipase CA induced the polymerization of divinyl esters of isoph-thalic acid, terephthalic acid, and p-phenylene diacetic acid with glycols to give polyesters containing aromatic moiety in the main chain.78 The highest molecular weight (7.2 x 103) was attained from a combination of divinyl isophthalate and 1,10-decanediol. Enzymatic polymerization of divinyl esters and aromatic diols also afforded the aromatic polyesters.79
A combinatorial approach for biocatalytic production of polyesters was demonstrated.80 A library of polyesters were synthesized in 96 deep-well plates from a combination of divinyl esters and glycols with lipases of different origin. In this screening, lipase CA was confirmed to be the most active biocatalyst for the polyester production. As acyl acceptor, 2,2,2-trifluoroethyl esters and vinyl esters were examined and the former produced the polymer of higher molecular weight. Various monomers such as carbohydrates, nucleic acids, and a natural steroid diol were used as acyl acceptor.
Lipase-catalyzed copolymerization of divinyl esters, glycols, and lactones produced ester copolymers with molecular weight higher than 1 x 104 (Scheme 5).81 Lipases BC and CA showed high catalytic activity for this copolymerization. 13 C NMR analysis showed that the resulting product was not a mixture of homopolymers, but a copolymer derived from the monomers, indicating that two different modes of polymerization, polycondensation and ring-opening polymerization, simultaneously take place through enzyme catalysis in one pot to produce ester copolymers. Furthermore, this result strongly suggests the frequent occurrence of transesterification between the resulting polyesters during the polymerization.
Acid anhydride derivatives are also good acylating reagents through lipase catalysis. A new type of enzymatic polymerization involving lipase-catalyzed ring-opening poly(addition-condensation) of cyclic anhydride with glycols was demonstrated (Scheme 6).82 The polymerization of succinic anhydride with 1,8-octanediol using lipase PF catalyst proceeded at room temperature to produce the polyester. Glutaric and diglycolic anhydrides were polymerized with a, w-alkylene glycols
in the presence of lipase CA in toluene to give the polyesters.83 Under appropriate reaction conditions, the molecular weight reached 1 x 104.
Polyester synthesis was carried out by insertion-dehydration of glycols into polyanhydrides using lipase CA as catalyst (Scheme 6).84 The insertion of 1,8-octanediol into poly(azelaic anhydride) took place at 30-60°C to give the corresponding polyester with molecular weight of several thousands. Effects of the reaction parameters on the polymer yield and molecular weight were systematically investigated.83 The dehydration reaction also proceeded in water. The reaction behaviors depended on the monomer structure and reaction media.
Lipase-catalyzed synthesis of polyesters from cyclic anhydrides and oxi-ranes was reported.85 86 The polymerization took place by PPL catalyst and the molecular weight reached 1 x 104 under the selected reaction conditions. During the polymerization, the enzymatically formed acid group from the anhydride may open the oxirane ring to give a glycol, which is then reacted with the anhydride or acid by lipase catalysis, yielding the polyesters.
Oxyacids or their esters were enzymatically polymerized to produce the corresponding polyesters. Polyesters of relatively high molecular weight were enzy-matically produced from 10-hydroxydecanoic acid87 and 11-hydroxyundecanoic acid88 using a large amount of lipase CR catalyst (10 weight fold for the monomer). In the case of 11-hydroxyundecanoic acid, the corresponding polymer with molecular weight of 2.2 x 104 was obtained in the presence of activated molecular sieves.
Lipase CA also polymerized hydrophobic oxyacids efficiently.89 The DP value was beyond 100 in the polymerization of l6-hydroxyhexadecanoic acid, 12-hydroxydodecanoic acid, or 10-hydroxydecanoic acid under vacuum at high temperature (90°C) for 24 h, whereas the polyester with lower molecular weight was formed from 6-hydroxyhexanoic acid under similar reaction conditions. This difference may be due to the lipase-substrate interaction.
Lipase-catalyzed polymerization of oxyacid esters was reported. PPL catalyzed the polymerization of methyl 6-hydroxyhexanoate.20 The polymer with DP up to 100 was synthesized by polymerization in hexane at 69°C for more than 50 days. The PPL-catalyzed polymerization of methyl 5-hydroxypentanoate for 60 days produced the polymer with DP of 29. Solvent effects were
systematically investigated; hydrophobic solvents such as hydrocarbons and diiso-propyl ether were suitable for the enzymatic production of high molecular weight polymer.
Ester-thioester copolymers were enzymatically synthesized (Scheme 7).90 The lipase CA-catalyzed copolymerization of e-caprolactone with 11-mercaptoundecanoic acid or 3-mercaptopropionic acid under reduced pressure produced the polymer with molecular weight higher than 2 x 104. The thioester unit of the resulting polymer was lower than the feed ratio. The transesterification between poly(e-caprolactone) and 11-mercaptoundecanoic acid or 3-mercaptopropionic acid also took place by lipase CA catalyst. Recently, aliphatic polythioesters were synthesized by lipase CA-catalyzed polycondensation of diesters with 1,6-hexanedithiol.91
Enzymatic synthesis of polyesters in green solvents such as supercritical fluids and ionic liquids were demonstrated. Supercritical carbon dioxide (scCO2) was employed as solvent for the polycondensation of divinyl adipate and 1,4-butanediol.92 Quantitative consumption of both monomers was achieved to give the polyester with molecular weight of 3.9 x 103, indicating that scCO2 was a good medium for the enzymatic polycondensation. The polymerization of bis(2,2,2-trichloroethyl) adipate and 1,4-butanediol using PPL catalyst proceeded in a supercritical fluoroform solvent to give the polymer with molecular weight of several thousands.93 By changing the pressure, the low-dispersity polymer fractions were separated.
Room-temperature ionic liquids have received much attention as green designer solvents. We first demonstrated that ionic liquids acted as good medium for lipase-catalyzed production of polyesters. The polycondensation of diethyl adipate and 1,4-butanediol using lipase CA as catalyst efficiently proceeded in 1-butyl-3-methylimidazolinium tetrafluoroborate or hexafluorophosphate under reduced pressure.94 The polymerization of diethyl sebacate and 1,4-butanediol in 1-butyl-3-methylimidazolinium hexafluorophosphate took place even at room temperature in the presence of lipase BC.95
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