Chemoenzymatic polymerization

The mechanism of catalysis of green biocatalysts and metal catalysts is quite different, but if booth are mutually compatible, then it allows the application concurrently in the same reaction system. The combination of these different types of catalysts is also addressed as chemoenzymatic method. Utilizing the advantages of enzymes, the chemoenzymatic method has been developed for the synthesis of various block copolymers, which are otherwise difficult to prepare. 

The combination of the lipase catalyzed ring-opening pol5mcier-ization of lactones and the atom transfer radical pol5mcierization allows a versatile S5mthesis of block copol5maers consisting of a polyester chain and a vinyl polymer chain (65). Also branched polymers have been produced by the chemoenzymatic technique (66). 

Cyclodextrins can polymerize cyclic esters such as lactones and lac-tides (67). They can initiate the polymerization of cyclic esters in bulk without any solvents to give products in high yields. 

It has been found that cyclodextrins are active not only as initiators catalysts but also they are supporting certain architectures of the final product similar to chaperone proteins. 

Chaperones are proteins that assist the folding or unfolding process and thus the assembly or disassembly of other macromolecular 

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Chemoenzymatic polymerizations have the potential to further increase macro-molecular complexity by overcoming these limitations. Their combination with other polymerization techniques can give access to such structures. Depending on the mutual compatibility, multistep reactions as well as cascade reactions have been reported for the synthesis of polymer architectures and will be reviewed in the first part of this article. A unique feature of enzymes is their selectivity, such as regio-, chemo-, and in particular enantioselectivity. This offers oppormnities to synthesize novel chiral polymers and polymer architectures when combined with chemical catalysis. This will be discussed in the second part of this article. Generally, we will focus on the developments of the last 5-8 years. Unless otherwise noted, the term enzyme or lipase in this chapter refers to Candida antarctica Lipase B (CALB) or Novozym 435 (CALB immobilized on macroporous resin). 

Figure 12.7 Two-step chemoenzymatic polymerization of PFOMA-b-PCL block copolymer [19].

Heise, A. Peeters, J. Xiao, Y. Palmans, A.R.A. Koning, C. Cross-linked polymers by chemoenzymatic polymerization ACS Polymer Preprints, 2006, 47(2), 224. 

Keywords Polyesters Lipase Polycondensation Ring opening polymerization Block copolymers Chemoenzymatic polymerization Chiral polymers... 

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 (3-malolactonate, followed by the debenzylation. The molecular weight of poly(benzyl (3-malolactonate) increased on copolymerizafion with a small amount of (3-PL using lipase CR catalyst. ... 

Chemoenzymatic synthesis of alkyds (oil-based polyester resins) was demonstrated. PPL-catalyzed transesterification of triglycerides with an excess of 1,4-cyclohexanedimethanol mainly produced 2-monoglycerides, followed by thermal polymerization with phthalic anhydride to give the alkyd resins with molecular weight of several thousands. The reaction of the enzymatically obtained alcoholysis product with toluene diisocyanate produced the alkyd-urethane. 

A novel chemoenzymatic route to polyester polyurethanes was developed without employing highly toxic isocyanate intermediates. First, diurethane diols were prepared from cyclic carbonates and primary diamines, which were subsequently polymerized with dicarboxylic acids and glycols by using lipase CA as catalyst, yielding the polyurethanes under mild reaction conditions. 

Chemoenzymatic synthesis of biodegradable poly(malic acid) was performed by lipase-catalyzed polymerization of benzyl /J-malolactone, followed by the debenzylation [72]. The addition of a small amount of /J-PL (17 mol % for the monomer) increased Mw up to 3 x 104 [73]. 

Hydrolases in Polymer Chemistry Chemoenzymatic Approaches to Polymeric Materials... 

Crosslinking of polymers is usually applied to stabilize the macroscopic morphology or shape of a material. In most cases, it results in insoluble polymeric materials, e.g., for polymeric coatings. In the chemoenzymatic strategies towards polymer networks, the enzymatic step is exclusively applied to synthesize the... 

Following route A (Fig. 1), Yan Xiao et al. reported the chemoenzymatic synthesis of poly(8-caprolactone) (PCL) and chiral poly(4-methyl-8-caprolactone) (PMCL) microparticles [5]. The telechelic polymer diol precursors were obtained by enzymatic polymerization of the corresponding monomers in the presence of hexanediol. Enzymatic kinetic resolution polymerization directly yielded the (R)-and (S )-enriched chiral polymers. After acrylation using acryloylchloride, the chiral and nonchiral particles were obtained by crosslinking in an oil-in-water emulsion photopolymerization. Preliminary degradation experiments showed that the stereoselectivity of CALB is retained in the degradation of the chiral microparticles (Fig. 2). 

Various a-methylenemacrolides were enzymatically polymerized to polyesters having polymerizable methacrylic methylene groups in the main chain (Fig. 3, left). The free-radical polymerization of these materials produced crosslinked polymer gels [10, 12]. A different chemoenzymatic approach to crosslinked polymers was recently introduced by van der Meulen et al. for novel biomedical materials [11]. Unsaturated macrolactones like globalide and ambrettolide were polymerized by enzymatic ROP. The clear advantage of the enzymatic process is that polymerizations of macrolactones occur very fast as compared to the chemically catalyzed reactions [13]. Thermal crosslinking of the unsaturated polymers in the melt yielded insoluble and fully amorphous materials (Fig. 3, right). 

Fig. 3 Chemoenzymatic routes to crosslinked macrolactones. Left enzymatic polymerization of a-methylenemacrolides and subsequent vinyl polymerization [10]. Right Enzymatically synthesized highly crystalline poly(ambrettolide) before and after thermal crosslinking [11]...

Fig. 4 Chemoenzymatic strategies (a—c) for the synthesis of block copolymers employing enzymatic ROP and radical polymerization techniques...

The second strategy for the chemoenzymatic synthesis of block copolymers from enzymatic macroinitiators employs an individual modification step of the enzymatic block with an initiator for the chemical polymerization (route B in Fig. 4). This strategy has the advantage that it does not depend on a high incorporation rate of the dual initiator. On the other hand, quantitative end-functionalization becomes more... 

Scheme 4 One-pot chemoenzymatic cascade polymerization combining enzymatic ROP and NMP for the synthesis of (chiral) block copolymer [43]...

Apart from ATRP, the concept of dual initiation was also applied to other (controlled) polymerization techniques. Nitroxide-mediated living free radical polymerization (LFRP) is one example reported by van As et al. and has the advantage that no further metal catalyst is required [43], Employing initiator NMP-1, a PCL macroinitiator was obtained and subsequent polymerization of styrene produced a block copolymer (Scheme 4). With this system, it was for the first time possible to successfully conduct a one-pot chemoenzymatic cascade polymerization from a mixture containing NMP-1, CL, and styrene. Since the activation temperature of NMP is around 100 °C, no radical polymerization will occur at the reaction temperature of the enzymatic ROP. The two reactions could thus be thermally separated by first carrying out the enzymatic polymerization at low temperature and then raising the temperature to around 100 °C to initiate the NMP. Moreover, it was shown that this approach is compatible with the stereoselective polymerization of 4-MeCL for the synthesis of chiral block copolymers. 

Extension of DKR to polymer chemistry would readily result in chiral polyesters, polycarbonates, or polyamides from an optically inactive monomer mixture. Scheme 10 describes three variants of chemoenzymatic catalysis applied in polymer chemistry that recently appeared in the literature. Route A uses AA and BB monomers to prepare chiral polymers from racemic/diasteromeric diols. Route B converts an enantiomer mixture of AB monomers to homochiral polymers. Route C is the enzymatic ring-opening polymerization of co-methylated lactones to homochiral polyesters. Details will be given in Sect. 3.4.2. 

Chapter 4 shows that the range of polymeric structures from enzymatic polymerization can be further increased by combination with chemical methods. The developments in chemoenzymatic strategies towards polymeric materials in the synthesis of polymer architectures such as block and graft copolymers and polymer networks are highlighted. Moreover, the combination of chemical and enzymatic catalysis for the synthesis of unique chiral polymers is discussed. 

X. Chen, A. Johnson, J. S. Dordick, and D. G. Rethwisch, Chemoenzymatic synthesis of linear poly(sucrose acrylate) Optimization of enzyme activity and polymerization conditions, Macromol. Chem. Phys., 195 (1994) 3567-3578. 

Combining whole-cell biocatalysis and radical polymerization, researchers at Imperial Chemical Industries (ICI) published a chemoenzymatic route to high-molecular-weight poly(phenylene) [86], This polymer is used in the fibers and coatings industry. However, since it is practically insoluble, the challenge was to make a soluble polymer precursor that could first be coated or spun, and only then converted to poly(phenylene). The ICI process starts from benzene, which is oxidized by Pseudomonas putida cells to cyclohexa-3,5-diene-l,2-diol (see Figure 5.17). The... 

Chemoenzymatic synthesis of a water-soluble polycarbonate having pendent carboxyl groups on the polymer main chain was achieved by lipase-catalyzed polymerization of 5-methyl-5-benzyloxycarbonyl-l,3-dioxan-2-one (MBC), followed by debenzylation.186 The copolymerization of MBC with TMC using lipase PF catalyst produced the random copolycarbonate.187... 

Linear unsaturated and epoxidized polyesters via enzymatic polymerization were reported as well [58]. For this long-chain symmetrically unsaturated a,co-dicarboxylic acid dimethyl esters (C18, C20, C26) were synthesized using metathesis techniques from 9-decanoic, 10-undecanoic, and 13-tetradecanoic acid methyl esters, respectively. The dicarboxylic acid dimethyl esters were epoxidized via chemoenzymatic oxidation with hydrogen peroxide/methyl acetate and Novozym... 

Figure 6.7 E-Diketones are the most popular radical initiators for chemoenzymatic radical polymerization reactions.

A polynucleoside with an unnatural polymeric backbone was synthesized by SBP-catalyzed oxidative polymerization of thymidine 5 -p-hydroxyphenylacetate [59]. Chemoenzymatic synthesis of a new class of poly(amino acid), poly(tyrosine) containing no peptide bonds, was achieved by the peroxidase-catalyzed oxidative polymerization of tyrosine ethyl esters, followed by alkaline hydrolysis [60]. 

Heise, Palmans, de Geus, Villarroya and their collaborators (17,41,42) have been working on a chemoenzymatic cascade synthesis to prepare block copolymers. They combine enzymatic ring-opening polymerization (eROP) and atom transfer radical polymerization (ATRP). The synthesis of block copolymers was successful in two consecutive steps, i.e., eROP followed by ATRP. In the one-pot approach, block copolymers could be obtained by sequential addition of the ATRP catalyst, but side reactions were observed when all components were present from at the onset of reactions. A successful one-pot synthesis was achieved by conducting the reaction in supercritical carbon dioxide. 

Biocatalysis is a key route to both natural and non-natural polysaccharide structures. Research in this area is particularly rich and generally involves at least one of the following three synthetic approaches 1) isolated enzyme, 2) whole-cell, and 3) some combination of chemical and enzymatic catalysts (i.e. chemoenzymatic methods) (87-90). Two elegant examples that used cell-fi-ee enzymatic catalysts were described by Makino and Kobayashi (25) and van der Vlist and Loos (27). Indeed, for many years, Kobayashi has pioneered the use of glycosidic hydrolases as catalysts for polymerizations to prepare polysaccharides (88,91). In their paper, Makino and Kobayashi (25) made new monomers and synthesized unnatural hybrid polysaccharides with regio- and stereochemical-control. Van der Vlist and Loos (27) made use of tandem reactions catalyzed by two different enzymes in order to prepare branched amylose. One enzyme catalyzed the synthesis of linear structures (amylose) where the second enzyme introduced branches. In this way, artificial starch can be prepared with controlled quantities of branched regions. 

We investigated the chemoenzymatic synthesis of block copolymers combining eROP and ATRP using a bifunctional initiator. A detailed analysis of the reaction conditions revealed that a high block copolymer yield can be realized under optimized reaction conditions. Side reactions, such as the formation of PCL homopolymer, in the enzymatic polymerization of CL could be minimized to < 5 % by an optimized enzyme (hying procedure. Moreover, the structure of the bifunctional initiator was foimd to play a major role in the initiation behavior and hence, the yield of PCL macroinitiator. Block copolymers were obtained in a consecutive ATRP. Detailed analysis of the obtained polymer confirmed the presence of predominantly block copolymer structures. Optimization of the one-pot procedure proved more difficult. While the eROP was compatible with the ATRP catalyst, incompatibility with MMA as an ATRP monomer led to side-reactions. A successfiil one-pot synthesis could only be achieved by sequential addition of the ATRP components or partly with inert monomers such as /-butyl methacrylate. One-pot block copolymer synthesis was successful, however, in supercritical carbon dioxide. Side reactions such as those observed in organic solvents were not apparent. 

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