Department of Pharmacy, Mahatma Jyotiba Phule Rohilkhand University, Bareilly, Uttar Pradesh, India 243006
The integration of green chemistry principles into polymer synthesis has resulted in significant progress in creating sustainable and environmentally friendly materials. Among various green methods, enzymatic catalysis has become a powerful and selective approach for polymer formation under gentle conditions. This review explores the role of enzymatic catalysis in polymer synthesis, emphasizing its advantages, such as high selectivity, lower energy use, and minimal reliance on toxic reagents or solvents. Different classes of enzymes, including lipases and peroxidases, have been used to catalyse the production of polyesters, polyamides, and other bio-based polymers from renewable monomers. The review also covers how enzyme engineering, reaction media, and process optimization affect polymer yield, molecular weight, and functionality. By examining recent developments and challenges, the article underscores enzymatic catalysis as a promising and eco-friendly alternative to traditional polymerisation methods, supporting the goals of sustainable chemistry and circular material design.
Polymers are macromolecules composed of a large chain of monomer units. These Polymers play a crucial role in the preparation of various equipment made up of rubber, latex, and also play a role in the development and synthesis of novel Pharmaceutical drug delivery systems. The process of formation of Polymers from monomer units is known as Polymerization, and a chemical synthesis is required to form these Polymers. The increasing global demand for sustainable materials and environmentally responsible manufacturing has brought green chemistry to the forefront of polymer science. Conventional polymer synthesis often involves harsh reaction conditions, toxic catalysts, and non-renewable feedstock, resulting in environmental pollution and high energy consumption. Green chemistry offers a transformative framework to address these concerns by emphasizing principles such as the use of renewable resources, safer solvents, energy efficiency, and waste minimization. The field has received widespread interest in the past decade due to its ability to harness chemical innovation to simultaneously meet environmental and economic goals [1]
Within this context, enzymatic catalysis has emerged as a powerful green tool for polymer synthesis. Enzymes, as natural biocatalysts, operate under mild reaction conditions—typically ambient temperature, atmospheric pressure, and aqueous or benign organic solvents—making them inherently environmentally friendly. Their high chemo, regio, and stereo selectivity also enables precise control over polymer structure and functionality, which is often challenging to achieve with traditional chemical catalysts. The use of enzymes such as lipases and peroxidases has enabled the development of various bio-based polymers, including polyesters, polyamides, and polycarbonates, from renewable monomers. These enzymatic processes not only reduce the environmental impact of polymer production but also create new opportunities for designing biodegradable and recyclable materials. Moreover, advancements in enzyme engineering and process optimization continue to broaden the scope and effectiveness of enzymatic polymerizations. The synthesis of polymeric materials with unique properties can be achieved not only through polymerization reactions but also by modifying or functionalizing existing polymers. [2]
This review aims to provide a comprehensive overview of the role of enzymatic catalysis in the green synthesis of polymers, detailing current methodologies, key enzymes involved, substrate scope, and prospects in sustainable polymer chemistry. it also focuses on showing a brief reflection to the researchers for developing new synthetic approaches via Green Chemistry.
2. Candida antarctica Lipase B (CALB)
The mystery of this enzyme was solved in 1994, as shown in Figure 1. This enzyme is widely used in the synthesis of Polymers via the green chemistry method. This enzyme belongs to the α/β-hydrolase-fold superfamily. [3] This enzyme evolved from a common ancestor to catalyse the reaction, which includes, hydrolysis of esters, thioesters, peptides, epoxides, and alkyl halides, along with the cleavage of carbon bonds in hydroxynitriles. CALB is made of 317 amino acids and has a molecular weight of 33 kDa. The active site pocket of CALB, which is approximately 10Å x 4Å wide and 12 Å deep, the catalytic triad in which consists mainly of three amino acids that are Ser105-His224-Asp187. [4] Figure 1 represents the chemical structure of CALB.
Figure 1 Chemical structure of CALB
As a Catalyst, the CALB has been widely used for the last two decades in polymerization. This polymerization is based on two strategies: that are ring-opening polymerization of lactones and the other is, polycondensation-type reactions. Moreover, important chemical reactions, specifically, transesterification, Michael addition, and epoxidation, can be performed under much milder conditions, exploiting the catalytic activity of CALB. [5]
2.1 CALB-Catalysed Transesterification
Classical transesterification reactions can be catalysed by CALB. Generally, the transesterification reaction is known to be a reversible reaction, but shifting the equilibrium towards the product can be achieved by the removal of the side product. Another way is to reduce the nucleophilicity with the help of electron-withdrawing groups, and because of it, the use of enol esters such as vinyl or isopropenyl esters appears to be the most useful since they liberate unstable enols as by-products, which rapidly tautomerize to give the corresponding aldehydes or ketones (Scheme 1). Therefore, the reaction becomes completely irreversible. [6]
Yadav et al. compared the various lipases in the transesterification reactions of vinyl acetate with n-octanol. CALB was found to be the most effective lipase with heptane as the solvent in the reaction. [7] Acetaldehyde, which forms during the reactions with vinyl esters, is known to inactivate the lipases from Candida rugosa and Geotrichum candidum by forming a Schiff’s base with the lysine residues of the protein; however, most lipases, including CALB, tolerate the liberated acetaldehyde. [8]
Scheme 1: Transesterification of esters with alcohols: Reversible with an alkyl ester or a halogenated alkyl ester, and Irreversible with a vinyl ester.
Recently, Xiao et al. reported the enantioselective esterification of caffeic acid using CALB, as shown in Scheme 2. Regardless of the stereochemistry of the alcohol used, a 100% R isomer was selectively formed in this esterification reaction when a hydrocarbon, isopropyl ether, or 1,4-dioxane was used as the solvent. However, a 100% S isomer was obtained when THF was used as the solvent. [9]
Scheme 2- CALB-catalysed asymmetric synthesis of (R)-caffeic acid esters.
2.2 CALB-Catalyzed Michael Additions - A conjugate addition reaction, the Michael Addition reaction leads to the addition of a Carbon-Carbon bond or a carbon-heteroatom to form a product. The reaction occurs in a strong acidic or basic medium, leading to the generation of potentially hazardous by-products. Bhanage et al. have reported an efficient enzymatic protocol for the synthesis of β-amino esters via Michael addition of primary and secondary amines to acrylates using CALB as a biocatalyst. [10] The use of CALB in such reactions because to the high yield value of the desired product with the efficiency. These additions take place when α, β-unsaturated systems are used as the electrophile moiety and amines as the nucleophile substrate. The possible mechanism of this “promiscuous” activity of CALB in the reaction points out that the oxyanion hole (Thr40 and Gln106) of the active site stabilizes the negative charge of the transition state, while the His224-Asp187 pair facilitates proton transfer during the catalysis. [11] It was also found that the low polarity solvents facilitate the reaction by inducing interaction between the oxyanion hole and the carbonyl oxygen in the catalytic intermediate complex. Let us understand the mechanism of reaction step by step- in the first step, the Nitrile group of acrylonitrile is activated by the oxyanion hole (in the case of α-β-unsaturated Carbonyl compounds, the carbonyl group). In the next step, conjugate addition of the incoming nucleophile, i.e., Pyrrolidine, to the α-carbon of the Michael-acceptor takes place, resulting in an intermediate which is stabilized by both the histidine-aspartate pair and the oxyanion hole in the enzyme active site. [12] In the last step, the proton transfers from Pyrrolidine ring to the alpha carbon of acrylonitrile.
Scheme 3 Enzymatic Michael addition of diethylamine to α-Acrylated, ω-methacrylated EG in bulk.
2.3. CALB-Catalyzed Epoxidation- It was reported that epoxidation of alkenes was achieved under extremely mild conditions by employing peroxycarboxylic acids formed continuously in situ by lipase-catalyzed peroxidation of the corresponding carboxylic acids, as shown in Scheme 4.
A catalytic amount of octanoic acid was used to generate peroxycarboxylic acid with H2O2 in hexane to epoxidize alkanes in hexane. CALB was found to be the most effective, but Candida cylindracea, Humicola, and Pseudomonas also catalyzed the reaction
Scheme 4- CALB catalyzed epoxidation of olefins in the presence of hydrogen peroxide.
3. Enzyme Catalysis in Polymer End-Functionalization
In this discussion, we will explore the synthesis of different Polymers via CALB enzymatic catalysis, including transesterification and Michael Addition.
3.1. Poly (ethylene glycol) (PEG) PEG is known for its excellent biocompatibility, low toxicity, and non-immunogenicity, making it widely used in pharmaceuticals, cosmetics, biomedical devices, and drug delivery systems. [13,14] In pharmaceutical applications, PEG is often used as a solvent, plasticizer, or excipient, and in PEGylation—the process of attaching PEG chains to therapeutic proteins or drugs to enhance their solubility, stability, and circulation time in the body. In polymer chemistry, PEG can serve as a soft segment in copolymers, a macromolecular initiator in controlled/living polymerizations, or a crosslinking agent in hydrogels and other network structures. Its terminal hydroxyl groups enable functionalization, making PEG a crucial building block in the design of advanced materials. The –OH end group of the PEG is the small molecular mass in the structure, which is used to synthesise derivatives. Our group reported first the synthesis of quantitative end-functionalization of PEG catalyzed by CALB. The functionalization of PEG refers to the chemical reaction under solvent-free conditions at a temperature of 50 °C for 4 hours. The reaction occurs with the corresponding acyl donor (vinyl methacrylate, vinyl acrylate, and vinyl crotonate), in the presence of immobilized CALB. [15]
Scheme 5 shows the dicrotonation and diacrylation of PEG by CALB
The reason PEG-Br is frequently utilized as an intermediate for further functionalization is that halogens, particularly bromine, make good leaving groups. Thionyl bromide or phosphorus tribromide in toluene is typically used to brominate PEG. The application of enzymatic processes is a compelling substitute tactic. High efficiency, recyclability, and the capacity to react in mild, solvent-free conditions are just a few benefits of this "green" polymer chemistry technique. [16,17]
3.2 Polyisobutylene (PIB)
Polyisobutylene (PIB) is a synthetic polymer derived from the cationic polymerization of isobutylene (2-methylpropene), a gaseous hydrocarbon. It is a colourless, tasteless, and non-toxic polymer known for its unique combination of properties, including excellent gas barrier performance, chemical resistance, thermal stability, and low permeability to moisture and air. PIB is a member of the polyolefin family and is structurally characterized by a saturated hydrocarbon backbone, which contributes to its remarkable oxidative and UV stability. Recent developments have focused on functionalizing PIB to broaden its utility in high-performance materials, drug delivery systems, and specialty elastomers. The low reactivity of the polymer backbone poses challenges for modification, but innovations in living polymerization and end-group transformation have enhanced its versatility. Quantitative methacrylation of hydroxyl-terminated PIB and Glissopal was accomplished through CALB-catalyzed transesterification of vinyl methacrylate at 50 °C in hexane over 24 hours and without solvent in 2 hours. [18,19]
Scheme 6 Enzymatic functionalization of PIB-OH
3.3. Polysiloxanes-
Polysiloxanes, commonly known as silicones, are a class of synthetic polymers characterized by a backbone of alternating silicon (Si) and oxygen (O) atoms, typically represented by the repeating unit –[R?Si–O]–, where "R" denotes organic side groups such as methyl, phenyl, or vinyl. The Si–O backbone provides Polysiloxanes with unique flexibility and thermal stability, while the organic side groups can be tailored for various applications. Polysiloxanes are resistant to UV radiation, oxidation, moisture, and many chemicals, making them suitable for harsh environments. Commercially available polydimethylsiloxanes (PDMS). PDMS-monocarbinol and PDMS-dicarbinols were also quantitatively methacrylated under solventless conditions within 2 h in the presence of CALB. [20]
4. Regio- and Chemo selectivity in Enzyme-Catalyzed Polymer Functionalization-
Enzyme-catalyzed polymer functionalization has emerged as a powerful and environmentally friendly approach in modern polymer chemistry, offering high precision through excellent regio- and chemo selectivity. This unique selectivity allows enzymes to modify specific sites on a polymer chain without affecting other functional groups, a level of control that is often difficult to achieve using conventional chemical methods.
4.1 Regioselectivity refers to the enzyme's ability to selectively react at a specific position within a molecule or polymer chain. For example, lipases can catalyse the acylation of hydroxyl groups in polyesters or polysaccharides at primary over secondary positions, enabling site-specific functionalization without altering the overall polymer structure. This is particularly useful in tailoring surface properties or introducing bioactive groups in a controlled manner.
4.2 Chemo selectivity is the enzyme’s preference for one functional group over others in the same molecule. Enzymes like peroxidases and oxidases can selectively oxidize phenolic or aniline groups without affecting other sensitive moieties, which is valuable in designing functional coatings, conductive polymers, or targeted bio conjugation strategies. The natural selectivity of enzymes reduces the need for protecting groups, minimizes by product formation, and often eliminates the use of toxic reagents or harsh conditions. This makes enzyme-catalyzed functionalization not only efficient and precise but also aligned with the principles of green chemistry. Advances in enzyme engineering and immobilization have further expanded their utility, enabling the modification of synthetic polymers such as polyesters, poly ethers, and polysaccharides for biomedical, packaging, and electronic applications. [21]
CONCLUSION
From the above data in this article, we concluded the importance of Polymers in the field of Pharmaceutical industries, the role and advantages of Green Chemistry in the synthesis of Polymers over the conventional synthetic methods. The solvent-less approaches and effective yield value by using fewer reactants and less time are the advantages of synthesis by green chemistry. we also discussed the importance of CALB in common reactions like Michael addition, transesterification, and epoxidation. CALB, a lipase enzyme used to synthesize various polymers with an Effective yield value. Specifically, the synthesis of PEG, Polyisobutylene, and Polysiloxanes is shown by various schemes, and their mechanism of synthesis is discussed in detail. The role of chemo selectivity and regio selectivity in the synthesis of these polymers as a product.
CONFLICT OF INTEREST: None
REFERENCES
Rachit Kumar Saxena, Vaibhav Bhardwaj, Shivdev Singh, J Role of Green Chemistry in the Synthesis of Various Polymers via Enzymatic Catalysis, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 12, 451-459. https://doi.org/10.5281/zenodo.17798545
10.5281/zenodo.17798545
