Enzyme-Catalyzed Synthesis of Polyesters

Enzyme-Catalyzed Synthesis of Polyesters: Comparison

Please note this is a comparison between Version 2 by WANG HONG and Version 1 by WANG HONG.

聚酯是由酯键连接的多元酸和多元醇组成的聚合物。这种类型的聚合物在汽车、家具、涂料、包装和生物医学等各个行业中都有广泛的应用。合成聚酯的传统工艺主要采用金属催化剂在高温下聚合。这种情况可能存在金属残留物和不希望的副反应的问题。作为替代方案，酶催化聚合由于无金属残留物、令人满意的生物相容性和温和的反应条件而迅速发展。Polyester is a kind of polymer composed of ester bond-linked polybasic acids and polyol. This type of polymer has a wide range of applications in various industries, such as automotive, furniture, coatings, packaging, and biomedical. The traditional process of synthesizing polyester mainly uses metal catalyst polymerization under high-temperature. This condition may have problems with metal residue and undesired side reactions. As an alternative, enzyme-catalyzed polymerization is evolving rapidly due to the metal-free residue, satisfactory biocompatibility, and mild reaction conditions.

polyester
enzyme
enzyme-catalyzed
polymerization

1. 简介Introduction

聚酯是一种常见的高分子化合物，其特征是在链的一级结构中存在酯键，由含羟基化合物和含羧化合物逐渐缩聚而得Polyester is a common polymer compound characterized by the existence of ester linkages in the chain’s primary structure, obtained by the gradual polycondensation of hydroxyl-containing compounds and carboxyl-containing compounds [1，2 1,2]，在自然界中仅次于多糖、蛋白质和, which ranks fourth in nature after polysaccharides, proteins, and DNA，排名第四。近年来，一系列新型高分子材料因其无毒和稳定的特点而迅速发展，例如聚酯。聚酯主要分为热塑性饱和聚酯和热固性不饱和聚酯两大类。传统的饱和聚酯，包括聚对苯二甲酸丁二醇酯（PBT）和聚对苯二甲酸乙二醇酯（PET），具有高机械强度、耐磨性、耐腐蚀性和耐温性以及其他突出的性能，已被广泛用作合成纤维和工程塑料。随着“白色污染”的加剧，聚乳酸（PLA）、聚丁二酸丁二醇酯（PBS）和其他生物塑料已被设计和制造. In recent years, a series of new polymeric materials have been developed rapidly due to their non-toxic and stable characteristics, for instance, polyester. Polyester is mainly divided into two categories of thermoplastic saturated polyester and thermosetting unsaturated polyester. Traditional saturated polyesters, which include polybutylene terephthalate (PBT) and polyethylene terephthalate (PET) that have high mechanical strength, abrasion resistance, corrosion resistance, and temperature resistance, as well as other outstanding properties, have been widely used as synthetic fibers and engineering plastics. With the “white pollution” intensified, polylactic acid (PLA), polybutylene succinate (PBS), and other bioplastics have been designed and manufactured [3，4 3,4]。这些生物塑料具有良好的生物降解性、生物相容性和无毒特性，可作为医疗卫生行业替代传统塑料的替代材料. These bioplastics have good biodegradability, biocompatibility, and non-toxicity characteristic, and they can be an alternative material to replace traditional plastics in medical and healthcare industry [5，6 5,6]。同时，热固性不饱和聚酯除了在聚合物链中的酯键外，还由不饱和基团组成，当加入自由基引发剂和交联剂时，该基团负责交联过程。热固性聚酯是一种不溶性聚合物，具有高刚性、回弹性、耐腐蚀性和耐候性，作为涂料和粘合剂材料在各个行业中具有广泛的应用。目前，这两种聚酯主要采用化学聚合法合成。. Meanwhile, thermosetting unsaturated polyester consists of an unsaturated group in addition to ester linkages in the main polymer chain, which is responsible for crosslinking process when a free radical initiator and crosslinker are added. Thermosetting polyester is an insoluble polymer with high rigidity, resilience, corrosion resistance, and weatherability, which has a wide range of applications in various industries as coatings and adhesive materials. At present, both types of polyester are mainly synthesized using the chemical polymerization method.

2. Current 目前的聚酯合成方法及可能的替代方案

通过化学合成路线生产聚酯的过程需要高温（

Polyester Synthesis Method and a Possible Alternative

The process of producing polyester via the chemical synthesis route requires a high temperature (above 180 °C以上），这可能导致过度氧化甚至显着破坏产品性能的稳定性。当使用具有低热稳定性或化学稳定性的单体时，如此高的反应温度会产生不希望的副反应。因此，这种聚合方法限制了可以形成的聚合物类型) which may lead to excessive oxidation or even significantly damage the stability of product performance. Such high reaction temperatures would produce undesirable side reactions when using monomers with low thermal or chemical stability. As a result, this polymerization method restricts the types of polymers that can be formed [7]。合成脂肪族聚酯的常规方法通常使用烷氧基铝、类锌和类锡金属氧化物或有机化合物作为催化剂. Conventional methods for synthesizing aliphatic polyesters usually use alkoxy aluminum, zinc-like, and tin-like metal-containing oxides or organic compounds as catalysts [8，9，10 8,9,10]。这种有毒金属催化剂如果在制造聚合物的过程中无法去除，通常会对最终产品的生物安全性和生物相容性产生负面影响。此外，如果有机溶剂的管理不当，生产过程中的大量有机溶剂可能会造成环境污染（溶液聚合）。通常，烃类溶剂用于制造聚酯，例如二甲苯或苯，以避免聚合过程中的粘度积聚，并通过共沸蒸馏去除酯化过程中产生的水。聚酯也可以通过酶催化合成。诺贝尔奖获得者萨姆纳在. This toxic metal catalyst normally might negatively affect the biosafety and biocompatibility of the end product if it cannot be removed after the process of making the polymer. Additionally, a significant quantity of organic solvents in the production process may cause environmental pollution (solution polymerization) if the management of the organic solvent is inappropriate. Generally, the hydrocarbon solvent is used to manufacture polyester, such as xylene or benzene, to avoid the viscosity buildup during the polymerization and to remove water produced from the esterification process via azeotropic distillation.

Polyesters can also be synthesized by enzyme catalysis. The Nobel Prize Winner Sumner proved in 1947年证明酶是具有催化特性的蛋白质 that enzymes are proteins with catalytic properties [11]。一些研究还发现，酶具有催化效率高、反应条件温和、无毒、可重复使用等优点. Some studies also discovered that enzymes have the advantages of high catalytic efficiency, mild reaction conditions, nontoxicity, and reusability [7，12 7,12]。近年来，由于功能性有机高分子材料的发展和酶催化剂的明显优势，酶催化有机大分子的合成得到了积极的研究，其中酶催化聚合是聚酯生产的重要途径. In recent years, owing to the development of functional organic polymer materials and the apparent advantages of enzyme catalysts, enzyme-catalyzed synthesis of organic macromolecules has been actively researched, where enzyme-catalyzed polymerization is an essential route for polyester production [13]。由于几个优点，以前已经进行了许多使用酶法生产聚酯的研究，例如（.

There are many studies have been previously conducted to produce polyester using an enzymatic process due to several advantages, such as (i) enzymes are deri）酶可从可再生资源中获得vable from renewable resources;（ii）可以避免原材料或产品热降解的温和反应条件;（iii）无金属催化剂残留，使产品达到更好的生物相容性;（iv）立体选择性、区域选择性和化学选择性，通常只有单个底物或一类结构相似的底物可以参与反应，保留其他基团单体的活性功能，避免不必要的副反应 (ii) mild reaction conditions where thermal degradation of the raw materials or product can be avoided; (iii) no metal catalyst residue which makes the product achieve better biocompatibility; (iv) stereoselective, regioselective, and chemoselective, usually only a single substrate or a class of structurally similar substrates can participate in the reaction, retaining the active function of other groups of the monomer, avoiding unwanted side reactions [14];（ and (v) biodegradable polyester can be synthesized using enzymes as a catalyst. As a comparison with chemical methods, enzyme-catalyzed polymerization of polyesters is a green process, which may be considered an alternative route for polyester synthesis. This process is seen as promising to resolve some issues caused by polyester synthesis, such as the disposal of unwanted side reactions as well as the metal catalyst residues. Additionally, the process may have added-value if the synthesis involves renewable resources and materials.

However, enzyme-catalyzed synthesis may have disadv）可生物降解的聚酯可以使用酶作为催化剂合成。与化学方法相比，酶催化聚酯聚合是一种绿色过程，可以被认为是聚酯合成的替代途径。该工艺被认为有望解决由聚酯合成引起的一些问题，例如处理不需要的副反应以及金属催化剂残留物。此外，如果合成涉及可再生资源和材料，该过程可能具有附加值。然而，酶催化合成可能存在成本高、酶消耗量大以及可生产的高分子量聚合物数量较少等缺点antages such as high cost, large enzyme consumption, and a lesser number of high molecular weight polymers that can be produced [15]。随着酶催化聚酯合成的发展，人们相信，当进行更多的尝试时，这些挑战将得到解决。 . With the development of the enzyme-catalyzed synthesis of polyesters, the challenges are believed to be addressed when more attempts are conducted. The current research on enzyme-catalyzed polymerization of polyesters mainly focuses on the types of enzymes and polymerization methods. This article focuses on the main routes of enzyme-catalyzed polyester synthesis and the increasingly attractive lipase catalysts used for polymerization, summarizes the progress of enzyme-catalyzed polyester synthesis in different solvent systems, and discusses the development trend to provide a comprehensive reference for further research.

3. Enzyme-Catalyzed 酶催化合成聚酯Synthesis of Polyesters

酶催化聚酯机理涉及几种类型的反应，包括酶催化开环聚合（There are several types of reaction involved in the enzyme-catalyzed polyester mechanism, including enzyme-catalyzed ring-opening polymerization (eROP），酶催化缩聚及其组合。), enzyme-catalyzed polycondensation, and their combination.

3.1. Enzyme-Catalyzed 酶催化开环聚合Ring-Opening Polymerization

自The eROP has been widely studied since the new type was first reported in 1993年首次报道 [16,17]; some simple eROP以来， are shown scheROP已被广泛研究[16，17];图matically in Figure 1. 示意性地显示了一些简单的 eROP。环状酯（内酯）可以通过eROP容易聚合，反应过程中不产生酒精或水。因此，无需考虑副产物去除技术，可产生高分子量产物Cyclic esters (lactones) can be easily polymerized via eROP, and no alcohol or water is produced during the reaction. Thus, no by-product removal techniques need to be considered, and a high molecular weight of the product could be yielded [18，19，20，21 18,19,20,21]。. Lars van der me等人Mee et al. [22]使用 achieved the polymerization of lactones with 6- to 13- and the 16-membered ring using Novozym 435通过eROP催化实现了内酯与6至13元和16元环的聚合。合成聚酯的数均分子量（Mn）范围为 as catalyze via eROP. The number average molecular weight (Mn) of the synthesized polyesters ranged from 6600 g/mol至23， to 23,600 g/mol。还发现. It was also found that Novozym 435对所有内酯具有相似的亲和力，催化大环内酯的聚合速率大于小环内酯。此外，大环大小的内酯的eROP可以被脂肪酶催化，这是金属催化方法难以实现的 has a similar affinity for all lactones, and the polymerization rate of catalytic macrocyclic lactones is greater than that of small cyclic lactones. In addition, the eROP of large ring-size lactones can be catalyzed by lipases, which is difficult to achieve by metal catalysis methods [23]。. Manzini等人 et al. [24] successfully polymerized more than a dozen giant macrolides (minimum 12-membered ring, maximum 84]在70°C下通过南极念珠菌脂肪酶-membered ring) via Candida antarctica lipase B（ (CALB）催化的eROP成功聚合了十几种巨型大环内酯类（最小12元环，最大84元环），聚合时间更长可以获得分子量更高的产物。此外，)-catalyzed eROP at 70 °C, and products with higher molecular weights can be obtained with longer polymerization times. Furthermore, eROP允许两种或多种不同的环状单体共聚。 allows for the copolymerization of two or more different cyclic monomers. Srivastava等人 et al. [25]通过脂肪酶CA催化的 synthesized a high molecular weight copolymeROP在60°C下合成了1，5-二氧杂环戊烷-2-酮（DXO）和ε-己内酯（CL）的高分子量共聚物。扫描电子显微镜（SEM）分析表明，共聚物的支架具有高度多孔性，并且包含相互连接的孔隙。样品的多孔结构大大改变了不含有毒金属残留物的支架的拉伸和粘弹性特性。众所周知，聚内酯因其优异的生物降解性和生物相容性而广泛应用于制药、生物医学和包装领域r of 1,5-dioxepan-2-one (DXO) and ε-caprolactone (CL) through Lipase CA-catalyzed eROP at 60 °C. Scanning electron microscopy (SEM) analysis showed that the scaffolds of the copolymer were highly porous and contained interconnected pores. The porous structure of the samples considerably altered the tensile and viscoelastic characteristics of the scaffolds which are free from toxic metallic residue. As known, polylactones are widely applied in the pharmaceutical, biomedical, and packaging sectors because of their excellent biodegradability and biocompatibility [26，27，28 26,27,28]。随着对环保、安全、无毒以及随后的功能化聚内酯的需求不断增长，内酯的. With the growing demand for environmentally friendly, safe, non-toxic, and subsequently, functionalized polylactones, the eROP作为传统合成方法的替代方法越来越受到关注 of lactones is gaining attraction as an alternative method to traditional synthesis methods [29，30，31，32 29,30,31,32]。.

图Figure 1.（ The eROP of (i）内酯，（) lactones, (ii）不同内酯的) different lactoneROP。x和y表示直链或支链中的碳原子数，x，y>0。s. x and y represent the number of carbon atoms in straight-chain or branched-chain, x, y > 0.

3.2. 酶催化缩聚Enzyme-Catalyzed Polycondensation

在In the early 1980年代早期，首次报道了酶催化缩聚反应s, the first enzyme-catalyzed polycondensation was reported [33，,34]，从那时起，脂肪酶就被认为是生产聚合物材料的重要工具。酶催化缩聚在聚合中起着至关重要的作用，因为单体可以具有广泛的选择性，并且产物也可以具有多样性, and ever since, lipases have become recognized as significant tools for polymer material production. Enzyme-catalyzed polycondensation plays a crucial role in polymerization as the monomers could have a wide range of selectivity, and the products could also have diversity [7]，如图, as schematized in Figure 2所示。羟基酸作为含有一个羟基和一个羧基的简单单体，可以通过酶催化缩聚聚合为聚羟基链烷酸酯（. Hydroxy acids, as simple monomers containing one hydroxyl group and one carboxyl group, can be polymerized to polyhydroxyalkanoates (PHA）。Ohara等s) by enzyme-catalyzed polycondensation. Ohara et al. [35]利用 studied the enzymatic polycondensation of lactic acid using Novozym 435研究了乳酸的酶缩聚反应，得到了高产低聚PLA。二元醇和二元酸的酶缩聚反应是普遍研究的，例如, and the high-yield oligomeric PLA was obtained. The enzymatic polycondensation of diols and diacids is commonly studied, for example, Mahapatro A等 et al. [36]使用 used CALB催化己二酸和辛二醇在70°C下缩聚24 h，产物的Mn可以达到17， to catalyze the polycondensation of adipic acid and octanediol for 24 h at 70 °C, and the Mn of the product could reach 17,800 g/mol。同时，. Meanwhile, Mahapatro等人 et al. [37]在一项研究中比较了各种二元醇和各种二元酸的酶催化缩聚反应。结果表明，长链癸二酸与辛二酸的反应速度较快。同时，己二酸和辛二酸可以生产出其中分子量最高的聚合物。 compared the enzyme-catalyzed polycondensation of various diols and various diacids in a study. The results showed that the long-chain sebacic acid with octanedioic acid could be reacted faster as compared to others. Meanwhile, adipic acid and octanedioic acid could produce a polymer with the highest molecular weight among them. Daniel等人 et al. [38]使用 synthesized linear polyesters of hexadecanedioic acid and octanediol using the Novozym 435酶缩聚法合成了十六烷二酸和辛二醇的线性聚酯，以生产聚酯薄膜，发现聚酯薄膜具有多空表面，在医疗或制药领域具有潜在价值。酶缩聚反应也产生水或醇，沸点较低的醇比水更容易从反应体系中去除，从而推动平衡向催化方向发展，可以获得更高的分子量产物 enzymatic polycondensation method to produce polyester films, which were found to have multivacant surfaces, exhibiting potential value in medical or pharmaceutical fields. The enzymatic polycondensation reaction also produces water or alcohols, and the lower boiling point alcohols are easy to be removed from the reaction system than water, thus driving the equilibrium toward catalysis, and a higher molecular weight product could be obtained [39]。因此，为了使酶促缩聚反应更容易，常使用二元酸衍生物作为单体. Therefore, in order to make the enzymatic polycondensation reaction easier, diacid derivatives are often used as monomers [40，,41，,42，,43]。. Azim 等人et al. [44] 利用脂肪酶催化琥珀酸二乙酯和丁二醇的缩聚反应，分别在utilized lipase to catalyze the polycondensation of diethyl succinate and butanediol to produce PBS 80 °C 和 95 °C 的温度下进行两步反应后产生重均分子量（Mw）为 38，with a weight average molecular weight (Mw) of 38,000 g/mol 的 PBS。Jiang等after a two-step reaction at temperatures of 80 °C and 95 °C, respectively. Jiang et al. [45]利用琥珀酸二乙酯和衣康酸二甲酯作为二酸衍生物单体，与 utilized diethyl succinate and dimethyl itaconate as the diacid derivative monomers with 1，4-丁二醇一起，通过,4-butanediol to synthesize poly(butylene succinate-co-itaconate) (PBSI) via Novozym 435在真空条件下催化酶缩聚合成聚（丁二酸丁二醇酯-共衣康酸丁二酯）（435 catalyzed enzymatic polycondensation under vacuum condition to eliminate the alcohol generated by the reaction. PBSI），以消除反应产生的醇。得到 with an Mn含量达13， reaching 13,288 g/mol、90%的PBSI，不饱和基团保存良好。另一方面，超支化多元醇聚酯可以使用酶催化缩聚法由多元醇生产 with 90% yield was obtained, and the unsaturated group was well preserved. On the other hand, hyperbranched polyol polyester could be produced from polyol using the enzyme-catalyzed polycondensation method [46，,47，,48]。超支化多元醇聚酯是主要用于替代软组织的弹性体，甘油聚酯是研究最多的聚酯之一. Hyperbranched polyol polyesters are elastomers mainly used to replace soft tissues, and glycerol polyesters are among the most studied polyesters [49，,50]。. Kulshrestha等人 et al. [51]研究了甘油，己二酸和 studied the enzyme-catalyzed polycondensation of glycerol, adipic acid, and 1，8-辛二醇在不同持续时间（5分钟至42小时）的酶催化缩聚反应。结果表明，观察到单体之间存在显著的相互作用45分钟后。结果表明：支化甘油聚酯的生长发生在线性生长之后。,8-octanediol at different durations, ranging from 5 min to 42 h. The results indicated that a significant interaction between monomers was observed after 45 min. The results indicated that the growth of branched glycerol polyesters occurs after linear growth. Taresco等人 et al. [52]研究了 studied the Novozym 435催化甘油和己二酸二乙烯酯的缩聚反应，以在不同温度下生产聚甘油己二酸酯（PGA）。结果表明，当温度从50 °C升高到70 °C时，PGA的支化程度从5%增加到30%。根据 catalyzed polycondensation of glycerol and divinyl adipate to produce polyglycerol adipate (PGA) at different temperatures. The results showed that the degree of branching of PGA increased from 5% to 30% when the temperature was increased from 50 °C to 70 °C. According to Giovanni B等 et al. [53] the degree of branching of poly (glycerol sebacate) (PGS) can be adjusted to 53]，当癸二酸6% when the substrate ratio of sebacic acid/甘油的底物比在CALB催化的酶缩聚反应中增加到glycerol was increased to 1.5/1.0时，聚（癸二酸甘油）（PGS）的支化程度可以调节到56%。因此，可以通过调整底物比例来控制PGS的支化程度，以满足医疗应用的需要。酶缩聚提供了一种从许多生物基单体合成聚酯的更环保的方法，可以减少对环境和健康的影响，因此，酶缩聚近年来受到相当多的关注 in the CALB catalyzed enzymatic polycondensation reaction. Therefore, the degree of branching of PGS can be controlled by adjusting the substrate ratio to meet the needs of medical applications. Enzymatic polycondensation offers a greener way to synthesize polyesters from many bio-based monomers, which could reduce environmental and health impacts, and therefore, enzymatic polycondensation has received considerable attention in recent years [3，,4，,39，,54]。.

图Figure 2.酶催化的缩聚反应（ The enzyme-catalyzed polycondensation of (i）羟基酸，（) hydroxyacids, (ii）二醇和二元酸，以及（) diols and diacids, and (iii）二醇和二元酸衍生物。) diols and diacid derivatives.

3.3. 酶催化共聚Enzyme-Catalyzed Copolymerization

酶催化共聚可用于制备多嵌段共聚物（图Enzyme-catalyzed copolymerization can be employed to prepare multi-block copolymers (Figure 3），它可以在大范围内改变共聚酯的性能，以获得用于不同应用的聚合物材料。小林等), which can change the properties of copolyesters in a wide range to obtain polymer materials for different applications. Kobayashi et al. [55]研究了通过酶催化共聚聚合羧酸酐单体和乙二醇，获得了高产率的聚合物。在后来的研究中，羧酸酐单体扩大到包括各种二元酸的酸酐 had a study to polymerize carboxylic anhydride monomer and ethylene glycol via enzyme-catalyzed copolymerization, and a high yield of polymer was obtained. In later studies, carboxylic anhydride monomers were expanded to include anhydrides of various diacids [56，,57]。. Jiang等人 et al. [58]成功地使用 successfully used Novozym 435催化ω-十五内酯（PDL）、琥珀酸二乙酯和1，4-丁二醇的酶催化共聚，合成了新的三元聚酯。共聚物的Mn可以达到24， to catalyze the enzyme-catalyzed copolymerization of ω-pentadecalactone (PDL), diethyl succinate, and 1,4-butanediol to synthesize a new ternary polyester. The Mn of the copolymer could be reached 24,400 g/mol，聚合物在, and the polymer was stable up to 300 °C下稳定，失重小于0.1%。 with less than 0.1% weight loss.

图Figure 3.酶催化（ The enzyme-catalyzed copolymerization of (i）二醇和羧酸酐（) diols and carboxylic anhydride (ii）内酯、二醇和二元酸衍生物的共聚。) lactones, diols, and diacid derivatives.