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Enzymatic Synthesis of Poly(glycerol sebacate): Kinetics, Chain Growth, and Branching Behavior
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Enzymatic Synthesis of Poly(glycerol sebacate): Kinetics, Chain Growth, and Branching Behavior
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Cite this: Macromolecules 2020, 53, 18, 7925–7935
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https://doi.org/10.1021/acs.macromol.0c01709
Published September 11, 2020

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Abstract

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Immobilized Candida antarctica lipase B (CALB)-catalyzed polycondensation of glycerol and sebacic acid at mild reaction conditions resulted in branched poly(glycerol sebacate) (PGS). To understand how PGS chains grow and branch, the kinetics of the CALB-catalyzed polycondensation were studied. The influence of the reaction temperature, solvent, CALB amount, and sebacic acid/glycerol feed ratio on the poly(glycerol sebacate) (PGS) molecular weight, degree of branching, and glyceridic repetitive unit distribution was also investigated. PGS architecture changes from linear to branched with the progression of the reaction, and the branching results from the simultaneous CALB-catalyzed esterification and acyl migration. For reactions performed in acetone at the temperature range from 30 to 50 °C, the apparent rate constant increases from 0.7 to 1.5 h–1, and the apparent energy of activation of 32 kJ mol–1 was estimated. The higher mass average molecular weight (16 kDa) and degree of branching (41%) were achieved using the equimolar sebacic acid/glycerol feed ratio in acetone at 40 °C with a CALB amount of 13.6 wt % and in the presence of the molecular sieves.

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Introduction

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Poly(glycerol sebacate) (PGS) is one of the most studied polyesters based on glycerol. This is mainly due to its biocompatibility and biodegradability, which make it suitable for biomedical applications in areas such as tissue engineering, drug delivery, and surgical sealants. (1−3) PGS elastomers are nontoxic materials (4,5) with mechanical properties similar to those of biological soft tissue (6−8) and present in vitro and in vivo degradability (7,9) and shape-memory behavior. (10) They are also bioresorbable and biocompatible due to the endogenous nature of glycerol and sebacic acid, which are building blocks of glycerides and a natural intermediate metabolite of the oxidation of fatty acids, respectively. (4,11−14) Conventionally, PGS elastomers are prepared in a noncatalyzed two-step process: (i) polymerization at 120 °C under an inert gas flow for 24 h and (ii) crosslinking at 120 °C under vacuum for 48 h. (4,5) The PGS elastomer properties are generally modulated through the reaction parameters, such as reaction time and temperature. (2,7,15) However, few studies have addressed the relationship between the PGS structure and properties. (5) Given the harsh polymerization conditions, a fraction of glycerol is lost through evaporation, leading to significant deviations between the predicted and the experimental PGS properties. (5,7) Furthermore, PGS for biomedical applications must be prepared in the absence of conventional catalysts due to their biological toxicity. (1) In this condition, the reaction is slow, and to prevent gelation, only oligomers are formed in the polymerization step. (7,16)
Alternatively, three strategies have been developed for the synthesis of glycerol-based polyesters under milder reaction conditions: (i) ring-opening polymerization of diglycidyl sebacate prepared by the reaction of sebacoyl chloride and glycidol with sebacic acid catalyzed by tetrabutylammonium bromide in dioxane at 95 °C; (17,18) (ii) polycondensation between glycerol and sebacoyl chloride catalyzed by the diarylborinic acid catalyst in tetrahydrofuran in the presence of N,N-diisopropylethylamine at 70 °C; (19) and (iii) lipase-catalyzed polycondensation between glycerol and diacids/diesters performed both in bulk as well as in solution using solvents such as tetrahydrofuran and biphenyl ether in the temperature range from 40 to 90 °C. (20−31) Among these strategies, lipase-catalyzed polycondensation seems to be the lower toxic and most sustainable and environmentally friendly alternative for the preparation of linear and branched polyesters based on glycerol. (32)
The enzyme Candida antarctica lipase B (CALB) is commercially available in a form supported on acrylic resin, and it is reported to be “the most used enzyme catalyst in both academia and industry”. (33) This lipase is mainly used for (trans)esterifications, amidations, and hydrolysis reactions in the synthesis of surfactants, monomers, polymers, optically pure compounds, biolubricants, glycerides, and biodiesel. (33) CALB is an sn-1,3-specific lipase with higher reactivity toward primary hydroxyls than secondary ones. (34−36) It is capable of hindering the crosslinking of polyesters prepared from glycerol and diacids/diesters, even at a relatively high molecular weight, and of catalyzing one-pot polymerization at mild reaction conditions. (27,29) Moreover, its specificity and reactivity could be modulated through the control of reaction parameters such as temperature (22,25,31) and solvent. (37,38) These characteristics make CALB suitable as a catalyst for the preparation of PGS polymers. (1)Table S1 (Supporting Information) summarizes the main reports about the synthesis of glycerol-based polyesters via CALB-catalyzed polymerization and the structural features of the polyesters. Poly(glycerol adipate) is the most studied glycerol-based polyesters prepared via CALB-catalyzed polymerization. Generally, the reaction is conducted in the tetrahydrofuran solution at the temperature range from 40 to 70 °C using divinyl adipate as a precursor. (20,24,25,30,31) To the best of our knowledge, only Uyama et al. (25,39) and Lang et al. (40) reported the CALB-catalyzed synthesis of PSG, both performed reactions in a solvent-free medium.
Despite CALB’s positional specificity, the esterification of glycerol secondary hydroxyls occurs to some degree with the formation of trisubstituted glyceridic units and branching of the glycerol-based polyester. (20−31,40,41) The structures of these polyesters are generally composed of mono-, di-, and trisubstituted glyceridic repetitive units that are structurally similar to mono-, di-, and triglycerides. (30) Similarly, the esterification of secondary hydroxyls and the formation of mono-, di-, and triglycerides using Mucor miehei, an sn-1,3-specific lipase, as a catalyst for the synthesis of lipids from glycerol and fatty acids have been reported. (42) The formation of triglycerides is due to a side reaction, named acyl migration (A.M.), which occurs in parallel to esterification. Acyl migration is an intramolecular reaction that allows the exchange of the acyl ester group among the adjacent hydroxyl groups, and it is the main reason for the esterification of secondary hydroxyls of glycerol, giving rise to triglycerides. (42,43) As reported by You et al., (17,18) the control of the branching of PGS is an important strategy for the improvement of PGS elastomer mechanical properties. So far, the relationship among CALB selectivity and acyl migration causing branching during polycondensation reactions between glycerol and dicarboxylic acids/diesters has not been reported.
Therefore, this work concerns the synthesis of PGS via CALB-catalyzed polycondensation between glycerol and sebacic acid at mild reaction conditions, a kinetic study, and an understanding of the mechanism of the polymer chain growth and branching. The influence of the solvent, temperature, CALB amount, and sebacic acid/glycerol molar feed ratio on the polymer molecular weight, glyceridic repetitive unit distribution, and the degree of branching (DB) was investigated by gel permeation chromatography (GPC) and 1H NMR spectroscopy. The temporal evaluation of the PGS structure sheds light on some insights into the chain growth behavior of polyesters based on glycerol prepared by CALB catalysis and the role of both CALB selectivity and acyl migration in branch formation. Overall, these results could assist the development of strategies toward polymer architecture control.

Experimental Section

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Materials

Sebacic acid (99.0%, Sigma-Aldrich), lipase acrylic resin—CALB (lipase B from C. antarctica, ≥5000 U g–1, Sigma-Aldrich), and deuterated acetone (99.9% atom D, Sigma-Aldrich) were used without any treatment. Molecular sieves, 5 Å (spheres, 4–8 mesh, Sigma-Aldrich), were exhaustively washed with distilled water and dried in an oven at 400 °C for 4 h. Glycerol (≥99.5%, Sigma-Aldrich), tert-butanol (99.5%, Acros Organics), acetone (≥99.5%, LabSynth), and acetonitrile (≥99.5%, LabSynth) were kept under molecular sieves. Tetrahydrofuran (≥99.0%, Vetec) was dried using metallic sodium and benzophenone under reflux and argon flow; this was followed by distillation and storage in a closed bottle with molecular sieves.

CALB-Catalyzed Polycondensation

In a typical polycondensation procedure, 5.0 mmol (1.01 g) of sebacic acid, 5.0 mmol (0.46 g) of glycerol, 200 mg of CALB (13.6 wt % relative to monomers), 2.0 g of 5 Å molecular sieves (a 2-fold excess based on molecular sieves water sorption capability of ca. 20 wt %), and 5 mL of solvent (tetrahydrofuran, acetone, tert-butanol, or acetonitrile) were put in a 30 mL capped glass flask. The reaction was maintained under gentle magnetic stirring (150 rpm) at a desirable temperature (30, 40, 50, 60, or 70 °C) for 24 h. For the kinetic studies, aliquots of 100 μL were taken after 2, 4, 6, 8, 10, 12, and 24 h reaction times, dried under vacuum, and kept at −20 °C for posterior analyses. After 24 h, the reaction medium was filtered and washed with acetone. The solvent was removed by distillation under reduced pressure. The residue was dried under vacuum and kept at −20 °C. Polymer purification by precipitation was not performed before analyses. PGS is a colorless to a yellowish polymer with an oily to a sticky gel consistency, depending on the molecular weight.

Instrumental Methods

The number average molecular weight (Mn), mass average molecular weight (Mw), and molecular weight dispersity (Đ = Mw/Mn) of PGS were determined by gel permeation chromatography (GPC) performed on a Viscotek GPCmax VE2001 instrument equipped with a Viscotek TGuard 10 × 4.6 mm2 guard column and three Shodex KF-806M columns kept at 40 °C and using tetrahydrofuran as an eluent at a flow rate of 1.0 mL min–1. The detection was performed using a Viscotek VE3580 refractive index detector. PGS solutions in tetrahydrofuran were prepared at a concentration of 5.0 mg mL–1 and filtered in poly(tetrafluoroethylene) filters (0.45 μm) before analysis. Polystyrene (PS) standards (Viscotek, Malvern) with the molecular weight from 1050 to 3 800 000 g mol–1 were used to determine the relative molecular weight of the PGS. The software OmniSEC. 4.6.2 (Viscotec, Malvern) was used for data collection and processing.
Infrared (IR) spectroscopy analysis of PGS was performed using Agilent Cary 360 Fourier transform infrared (FTIR) equipment operating in an attenuated total reflectance mode, spectral range from 400 to 4000 cm–1, resolution of 4 cm–1, and 64 scans.
Proton nuclear magnetic resonance (1H NMR) analyses were performed on a Bruker Avance 400 MHz spectrometer operating at 25 °C, 2.0 s acquisition time, 1.0 s recycle delay, a spectra width of 8012 Hz, 16 scans, 32k points, and a free induction decay (FID) resolution of 0.49 Hz. Carbon nuclear magnetic resonance (13C NMR) analyses were performed on a Bruker Avance 500 MHz spectrometer operating at 25 °C, 1.0 s acquisition time, 60 s recycle delay, a spectra width of 32 894 Hz, 920 scans, 64k points, and an FID resolution of 1.0 Hz without the nuclear Overhauser enhancement. Analyses of multiplicity editing proton–carbon heteronuclear single quantum coherence spectroscopy (1H–13C HSQC) were performed on a Bruker Avance 400 MHz spectrometer operating at 25 °C using the pulse program hsqcedetgp, with proton and carbon acquisition parameters of 0.24 and 0.01 s acquisition time, spectra width of 4244 and 19 120 Hz, 2k and 0.5k points, FID resolution of 4.15 and 74.7 Hz, respectively, 1.0 s recycle delay, and 16 scans. Analyses of proton homonuclear correlation spectroscopy (1H–1H COSY) were performed on a Bruker Avance 400 MHz spectrometer operating at 25 °C using the pulse program cosygpqf, with acquisition parameters for each proton of 0.24 and 0.06 s acquisition time, 1.0 s recycle delay, a spectra width of 4244 Hz, 2k and 0.5k points, FID resolution of 4.1 and 16.6 Hz, and eight scans. PGS solutions in (CD3)2CO were used, and the chemical shifts (δ) in parts per million (ppm) were assigned to the residual solvent proton and carbon of the (CD3)2CO at δH = 2.05 ppm and δC = 206.26 ppm, respectively.
The software TopSpin version 3.6.1 (Bruker) was used for NMR spectra processing, signal assignments, integration, and deconvolution. The signal integration was performed using the integration tool with baseline correction. The deconvolution of signals was performed by defining peak positions and fitting the curve with Gaussian and Lorentzian functions.

Results and Discussion

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Structural Characterization of PGS

The IR spectrum of PGS (Figure S1) reveals the presence of bands centered at 3440, 1735, 1060, and 1090 cm–1, which are related to hydroxyl, carbonyl ester, and primary and secondary alcohol stretching vibrations, respectively. These bands prove the formation of polyester with primary and secondary hydroxyl pendant groups along the polymer chains. (22,31) The PGS is branched and composed of the terminal (1T and 2T), linear (1,3L and 1,2L), and dendritic (1,2,3D) glyceridic repetitive units, Figure 1a. The 1H NMR spectrum (Figure 1b) of PGS shows the characteristic signals of the sebacic acid/ester in the chemical shift region from 1.00 to 2.50 ppm, overlapped signals in the region from 3.30 to 4.50 ppm related to methine and methylene protons of glycerol and glyceridic repetitive units, and signals in the chemical shift range from 4.70 to 5.40 ppm related to methine protons of glyceridic repetitive units with secondary hydroxyl esterified (2T, 1,2L, and 1,2,3D). (5,19,22,44,45)

Figure 1

Figure 1. (a) Substitution pattern of PGS composed of the terminal (1T and 2T), linear (1,3L and 1,2L), and dendritic (1,2,3D) glyceridic units as indicated by the (b) 1H NMR spectrum in (CD3)2CO.

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The 13C NMR analysis (Figure S2) was also performed. The signals of glycerol and glyceridic repetitive units, in the chemical shift range from 55 to 80 ppm, were not overlapped; their assignments have been well established in the literature. (19,22,27,29,44,45) However, these signals are of very low intensity and, when performing a quantitative analysis without the nuclear Overhauser enhancement, the signal intensity is even lower and some signals could not be detected if the number of scans and the runtime were not high enough, a problem that does not take place in the 1H NMR spectra. (22) Thus, HSQC and COSY analyses (Figures S3 and S4, respectively) were performed to obtain a precise and detailed assignment of the signals in the 1H NMR spectrum. Data from the one-dimensional (1D) and two-dimensional (2D) NMR analyses show that the methine protons a (3.83 ppm), b (4.89 ppm), d (5.09 ppm), and e (5.29 ppm) of 1T, 2T, 1,2L, and 1,2,3D glyceridic units, respectively, present signals in the 1H NMR spectrum free of overlapping. Therefore, the areas of these signals were used to determine the average molar fraction (xi) of each glyceridic species (i) in the reaction medium, by normalizing it by the carbonyl signal area (f + f′). The molar fractions of the nonreacted glycerol and the 1,3L units were calculated using eqs S1–S3. An example of the evolution of 1H NMR spectrum signals during the CALB-catalyzed polycondensation of sebacic acid and glycerol can be found in Figure S5. The carboxylic acid conversion (pCOOH) was estimated by the relative areas of the signals f and f′ determined by curve-fitting of the overlapped signals (Figure S6 and eq S4, Supporting Information). The relative molar fraction of each glyceridic unit (yi) in the PGS chain was determined from the average molar fraction of each glyceridic species in the reaction medium (eq S5). The degree of branching (DB) was calculated as proposed by Frey et al. (46) using the relative molar fraction of each glyceridic unit, and the number average degree of polymerization (Dpn) of PGS was calculated based on Flory (47) and Frey (46) models for linear and branched polymers (eq S6). The number average molecular weight (Mn) and the average number of each glyceridic unit per PGS chain (ni) (eqs S7 and S8, respectively) were also estimated from Dpn. The degree of substitution (DS) of the glycerol and the hydroxyl conversion (pOH) were calculated from the average molar fraction of glyceridic units and DS values using eqs S9 and S10 (Supporting Information), respectively. The average molar fractions of each glyceridic unit estimated from 1H NMR and quantitative 13C NMR spectra were very close, as can be seen in Table S2, Supporting Information. Therefore, 1H NMR analysis is a valuable tool to follow the evolution of the polymer structure. It provides an estimate of the polymer number average molecular weight and the type of glyceridic units incorporated in the polymer over time. The overall results from GPC and 1H NMR are summarized in Tables S3–S6 as a function of the reaction time, temperature, and solvent, and they will be discussed below.

Effect of Solvent and Temperature on Polymerization and the PGS Structure

Except for the presence of the immobilized enzyme beads and molecular sieves, the reaction medium was homogeneous and clear at the beginning of the reaction in tetrahydrofuran. When acetone, acetonitrile, or tert-butanol was used as a solvent, a cloudy mixture was initially observed due to the lower solubility of sebacic acid in these solvents. However, after approximately 30 min, the reaction media became clear due to sebacic acid consumption by esterification. The carboxylic acid and hydroxyl conversion (pCOOH and pOH, respectively), the number average molecular weight, the mass average molecular weight, the molecular weight dispersity, the degree of branching, and the relative molar fraction of each glyceridic unit in the PGS chains are presented in Table 1 for polycondensation reactions carried out in different solvents for 24 h at temperatures from 30 to 70 °C.
Table 1. Structural Parameters of PGS Synthesized Using 13.6 wt % of CALB in Different Reaction Conditions for 24 h
        yi (%)a
solventT (°C)pCOOHapOHaMn (kDa)aMw (kDa)bĐbDB (%)a1T2T1,3L1,2L1,2,3D
tetrahydrofuran400.920.643.2105.638242391817
500.910.643.095.441233341818
600.870.611.974.634263401615
tert-butanol400.760.571.022.12534435189
500.790.571.132.02431439179
600.830.591.442.728284401711
700.830.591.442.728274411711
acetone300.940.643.8136.534212471516
400.970.669.4166.841193411720
500.940.654.9156.742213391720
acetonitrile400.820.591.433.133323351613
500.840.601.443.138283421512
600.950.612.753.431263421613
a

Determined by 1H NMR.

b

Determined by GPC.

The molar fraction of glyceridic units per PGS chain is similar regardless of the solvent and temperature. The relative molar fraction of glyceridic units with esterified primary hydroxyls (1T and 1,3L) was higher compared to those with an esterified secondary hydroxyl (2T and 1,2L), showing higher CALB reactivity toward glycerol primary hydroxyls. The highest carboxylic acid and hydroxyl conversions were observed for reactions performed in tetrahydrofuran and acetone, for which pCOOH > 90% and pOH > 60%, indicating that these solvents are suitable for CALB-catalyzed polycondensation reactions. The solvent selection guide CHEM21 (48) classifies acetone, tert-butanol, and acetonitrile as “recommended” solvents. On the other hand, tetrahydrofuran is classified as “problematic”. PGS with a higher molecular weight was obtained using acetone at 40 °C. In this condition, branched PGS with Mn, Mw, and DB up to 9.4 kDa, 16 kDa, and 41%, respectively, was formed. In the reactions performed in tetrahydrofuran at 40 °C, PGS molecular weights are smaller (Mn = 3.2 kDa and Mw = 10 kDa), with DB = 38%. For comparison, it has been reported that PGS molecular weights in the range of Mn = 4.6–6.5 kDa and Mw = 17.0–23.0 kDa were obtained using the conventional noncatalyzed process. (49,50) Moreover, Uyama et al. (25) reported that PGS with Mw = 19.0 kDa and y1,2,3D = 16% was prepared by the CALB-catalyzed polycondensation of vinyl sebacate and glycerol in bulk at 60 °C in an inert atmosphere for 8 h, and Lang et al. (40) reported PGS with Mw = 63.9 kDa (Đ = 16.9) by performing the CALB-catalyzed polycondensation of sebacic acid and glycerol in bulk at 90 °C under reduced pressure for 47 h. Therefore, our results demonstrated that CALB-catalyzed polycondensation between sebacic acid and glycerol using a low hazard acetone as a solvent, molecular sieves, and mild reaction conditions in a closed system is suitable for the preparation of PGS. Also, higher molecular weights were obtained from this process than by performing the reaction in tetrahydrofuran, and the molecular weights were similar to the results from using the conventional process or vinyl sebacate as a precursor.
The general rule for biocatalyzed reactions in organic solvents is that there is a decrease in biocatalyst activity with decreasing solvent log P (P = octanol/water partition coefficient). (51) This is due to the distortions of the enzyme structure caused by the interactions of the solvent molecules with the catalytic site or by solvent interacting and pulling out the essential water molecules that stabilize the enzyme. For esterification, the further release of these water molecules to the reaction medium could lead to hydrolysis reactions. (51−54) However, as observed in Table 1, a decrease in biocatalyst activity with decreasing solvent log P was not followed. This was independent of the temperature, and the increase in the molecular weight followed the order: acetone (log P = −0.23) > tetrahydrofuran (log P = 0.49) > acetonitrile (log P = −0.33) > tert-butanol (log P = 0.35). Therefore, the effect of solvent on the enzyme structure and its activity may not be the main factor responsible for the different PGS molecular weights. A possible explanation for the observed tendency could be polymer–solvent interactions. If the polymer–solvent interactions are not favorable during polymer chain growth, the polymer coil will contract or possibly even form aggregates (as will be shown further), which, in turn, will result in a decrease in the availability of polymer reactive groups to proceed toward polymerization.
As presented in Table 1 for reactions performed in tert-butanol and acetonitrile, the molecular weight tends to slightly increase as the temperature increases in the range from 40 to 70 °C. However, for acetone and tetrahydrofuran, an increase in the temperature of above 50 °C leads to a decrease in the molecular weight. This phenomenon is due to CALB thermal deactivation, as reported by Distel et al. (55) for the CALB-catalyzed polymerization of ethyl-S-lactate in tetrahydrofuran and chloroform and by Taresco et al. (31) for the polycondensation of glycerol and vinyl adipate in tetrahydrofuran at temperatures above 50 °C. It is worthwhile to observe that using apolar solvents or by performing reactions in bulk, the decrease of CALB activity at temperatures of around 50–60 °C was not observed, and successful polymerizations in these media at temperatures up to 90 °C have been reported (Table S1). (40,56−58)

Effect of the Enzyme Amount and Sebacic Acid/Glycerol Molar Feed Ratio on Polymerization and the PGS Structure

For reactions performed in acetone at 40 °C for 24 h, the increase in the enzyme amount from 3.4 to 13.6 wt % leads to an increase in Mn, Mw, Đ, and DB from 1.4 to 9.4 kDa, 3 to 16 kDa, 2.1 to 6.8, and 17 to 41%, respectively (Table 2). These results agree with the literature that CALB catalyzes esterification reactions according to the kinetic model Ping-Pong Bi-Bi, for which the reaction rate is proportional to the enzyme amount. (59,60) The highest enzyme concentration of 13.6 wt % used in this work aimed to achieve higher conversion in shorter reaction times. For the synthesis of glycerol-based polyester, the CALB amount of 10 wt % is generally employed in both solvent-free and in solution reactions. (22,23,27,29) However, Gameiro et al. (41) reported the use of a CALB amount of 25 wt % for the enzymatic synthesis of poly(glycerol succinate) in a supercritical carbon dioxide solution and the formation of polymers with Mn up to 3.5 kDa. Uyama et al. (25) reported the use of a CALB amount of 15 wt % for the synthesis of PGS with Mw = 19.0 kDa and y1,2,3D = 16% from vinyl sebacate in bulk at 60 °C for 8 h. These PGS molecular weight and the fraction of the dendritic unit are similar to those achieved by us when using a CALB amount of 13.6 wt % (Mw = 16 kDa and y1,2,3D = 20%). Although, these results were achieved in shorter reaction times than our experiments due to the higher reactivity of vinyl sebacate compared to sebacic acid.
Table 2. Structural Parameters of PGS Prepared Using Different Amounts of Enzyme and Sebacic Acid/Glycerol Feed Ratios in Acetone at 40 °C for 24 h
      yi (%)a
[enzyme] (wt %)molar feed ratioMn (kDa)aMw (kDa)bĐb (Da)DB (%)1T2T1,3L1,2L1,2,3D
13.61.0/1.09.4166.841193411720
10.21.0/1.05.4115.841222401620
6.81.0/1.03.7134.536222441516
3.41.0/1.01.432.1173025396
13.61.5/1.0n.d.c114.85680441236
13.61.2/1.0n.d.c84.054151371631
13.61.0/1.2n.d.c73.128313391611
13.61.0/1.5n.d.c31.71744633135
a

Determined by 1H NMR.

b

Determined by GPC.

c

n.d. = not determined.

PGS with a higher molecular weight was obtained in acetone at 40 °C in 24 h using an equimolar feed ratio sebacic acid/glycerol. Deviation from this molar ratio leads to a decrease in the molecular weight (Table 2). These results indicate that glycerol tends to act as a diol in the CALB-catalyzed polycondensation. This is in agreement with Yang et al. (29) and Rao et al., (22) who reported that CALB is capable of hindering crosslinking, and deviation from equimolarity between the monomers leads to a decrease in the molecular weight of poly(oleic diacid-co-glycerol) and poly(glycerol suberate), respectively. The high PGS molecular weight dispersity values (Đ > 2.0) observed in Table 2 may be explained by the difference in CALB reactivity toward primary and secondary hydroxyl, which leads to randomly branched polymers composed of the terminal, linear, and dendritic units instead of the formation of uniformly “perfect” dendrimers composed of only terminal and dendritic units. This structural randomness of PGS is associated with the high Đ value, as reported by Kulshrestha et al. (27) for the terpolymer of adipic acid, 1,8-octanediol, and glycerol synthesized via CALB catalysis. Rao et al. (22) have reported that the architecture of poly(glycerol suberate) can be changed from linear (Đ ≈ 2.0) to irregular like-dendrimers (Đ > 2.0) by changing the monomer feed ratio in the CALB-catalyzed polycondensation. Also, Table 2 shows that the higher the glycerol feed, the smaller is the formation of dendritic units, and more linear are the PGS chains. Furthermore, an increase in the sebacic acid feed from 1.0 up to 1.5 increased DB and decreased the average molar fraction of glyceridic end groups (y1T and y2T), whereas an increase in the glycerol feed from 1.0 up to 1.5 led to an opposite effect, a decrease in the DB and an increase in the average molar fraction of glyceridic end groups. Therefore, the change in the sebacic acid/glycerol feed ratio would be a strategy toward the control of the PGS structure by tailoring the polymer molecular weight, degree of branching, and end-group functionality.

Evaluation of the Temporal Evolution of PGS Molecular Weight

The influence of branching on the Mn determined by 1H NMR and GPC is shown in Figure 2a,b for PGS synthesized in acetone at 30 and 40 °C, respectively.

Figure 2

Figure 2. Degree of branching (DB) and the average number of dendritic units per PGS chain (n1,2,3D), determined by 1H NMR, and the number average molecular weight (Mn) as a function of reaction time as determined by 1H NMR and GPC analyses for reactions performed in acetone at (a) 30 °C and (b) 40 °C.

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The Mn values determined by 1H NMR and GPC are in agreement with oligomers having Mn ≤ 1.0 kDa, and the deviations occurred when PGS became branched, i.e., when the DB value is approximately 30% and every polymer chain seems to have at least one dendritic unit (n1,2,3D ≥ 1.0). The discrepancies between Mn values determined by these techniques increase with an increase in the number of dendritic units. It is well established that GPC analysis of branched polymers provides molecular weight values smaller than the real one because branched polymers have a more dense and compact polymer coils and a smaller hydrodynamic radius (Rh) than their linear analogues. Because of this, the Mn value determined from GPC is generally smaller than the value determined by 1H NMR. (27,61,62)
Despite the deviations of the molecular weight determined by GPC for branched polymers, this technique is a valuable tool to follow the relative molecular weight evolution and molecular weight distribution during the polymerization. Figure 3a,b,c,d illustrates the evolution of the GPC chromatograms for the reactions performed at 40 °C in tetrahydrofuran, tert-butanol, acetone, and acetonitrile, respectively.

Figure 3

Figure 3. GPC chromatograms illustrating the temporal evolution of the molecular weight and molecular weight distribution of the PGS prepared in (a) tetrahydrofuran, (b) tert-butanol, (c) acetone, and (d) acetonitrile at 40 °C. The dashed lines indicate the retention volume related to the PS standard with the lowest molecular weight (1050 g mol–1) at 33 mL.

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For all of the reaction conditions studied, an increase in the reaction time from 2 to 24 h led to a shift of the peaks in the chromatograms to a smaller retention volume (higher molecular weight), an enlargement of the molecular weight distribution, and the appearance of multimodal peaks, which are related to an increase in the structural complexity of randomly branched polymers due to the statistical character of chain growth. During polymer growth, the number of dendritic units increases and each dendritic unit gives rise to a new terminal unit. The high number of terminal units available during the polymerization makes possible the formation of structures with different sizes and architectures (more or less branched molecules). (27,61,62) In Figure 3c, a bimodal molecular weight distribution curve with peak maxima at retention volumes of around 32.5 and 26.0 mL is observed for PGS after 24 h reaction in acetone at 40 °C. The last peak (26.0 mL), corresponding to a very high molecular weight (approximately 100 kDa according to the calibration curve using PS standards), is assigned to polymer aggregates. Because of this, it was not considered in the estimation of the mass average molecular weight and molecular weight distribution. Similar results were observed for the reaction performed in acetone at 50 °C/24 h.
Dynamic light scattering (DLS) experiments were performed in conditions similar to those of GPC analyses to determine whether aggregation of PGS (Mn = 9.4 kDa) occurs in the tetrahydrofuran solution. The particle size distribution profile (Figure S7a) shows three particle populations in the PGS solution in tetrahydrofuran with concentrations ranging from 1 to 10 mg mL–1: (i) unimers with an Rh of 3–4 nm; (ii) aggregates with an Rh of 8–15 nm, and (iii) a second aggregate population with an Rh of 40–80 nm. A similar particle size distribution profile was reported by Murillo et al. (63) for hydroxylated hyperbranched polyester in dimethylformamide, for which a population of unimers with an Rh of 2–5 nm and aggregates with an Rh of 150–500 nm was observed. Xiang et al. (64) studied the self-assembly of amphiphilic hyperbranched polyurea in water and proposed a stepwise mechanism in which unimers with an Rh of 2–3 nm form micelles with an Rh of 6–14 nm. Furthermore, these micelles associate in larger aggregates with an Rh ≥ 100 nm. The interactions among hydroxylated polymeric chains were studied by Žagar and Grdadolnik, (65) who reported that hydroxylated hyperbranched polyester chains interact with each other by strong hydrogen bonds among hydroxyl groups and between hydroxyl groups and carbonyl ester groups, even in the presence of water. These strong interactions between the hydroxylated polymeric chains and the mechanism of self-assembly of amphiphilic polymers in solution could explain the PGS aggregation in tetrahydrofuran as observed by DLS and the presence of a population of high molecular weight molecules in the GPC chromatograms (Figure 3c). From the DLS analyses, the critical aggregation concentration (CAC) of PGS in tetrahydrofuran was estimated to be 0.74 mg mL–1 or 7.9 × 10–5 mol L–1, by plotting the mean scattering intensity as a function of the PGS concentration (Figure S7b). PGS aggregation occurred in all solvents studied, as verified by DLS experiments. The particle size distribution curves of the PGS solution in acetone, acetonitrile, and tert-butanol can be found in Figure S8, Supporting Information.

Kinetics of CALB-Catalyzed Polycondensation

The kinetic study of the enzymatic catalyzed polycondensation was performed in four different polar solvents (tetrahydrofuran, tert-butanol, acetone, and acetonitrile) in the temperature range from 30 to 70 °C. The determination of the apparent constant rate (kapp) for the polycondensation was performed as proposed by Flory, (47) assuming the following: (i) glycerol reacts as a diol and (ii) cyclization does not take place. The first assumption is supported by the CALB higher reactivity toward primary hydroxyls than the secondary ones. (34−36) The second assumption is supported by the work performed by Kline et al. (20) and by Godinho et al., (66) in which cyclic end groups were not observed and some degree of cyclization was only observed for tetramers, respectively, for glycerol-based polyesters prepared via CALB catalysis.
The Dpn vs t curves for the reactions performed in tetrahydrofuran, tert-butanol, acetone, and acetonitrile in the temperature range from 30 to 70 °C are presented in Figure 4a,b,c,d, respectively. The kapp was determined as the slope of the Dpn vs t curves and plotted as a function of the reaction temperature, as presented in Figure 4e.

Figure 4

Figure 4. Number average degree of polymerization (Dpn) as a function of reaction time for reactions performed in (a) tetrahydrofuran, (b) tert-butanol, (c) acetone, and (d) acetonitrile. (e) Apparent rate constant (kapp) as a function of temperature.

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The kapp values are similar for the reactions conducted in tetrahydrofuran and acetonitrile. A slight dependence of the reaction rate on the temperature is observed for reactions in these solvents with a decrease of the kapp from around 0.5 to 0.2 h–1 when the reaction temperature was increased from 40 to 60 °C. tert-Butanol was the worst solvent for the preparation of PGS, for which a Dpn of around 4–5 and kapp around 0.1 h–1 were achieved for reactions performed in the temperature range from 40 to 70 °C for 24 h. Using acetone as a solvent, Dpn and kapp achieved the highest values. The polycondensation performed at 30, 40, and 50 °C resulted in PGS with Dpn of 15, 36, and 19 and kapp of 0.7, 1.2, and 1.5 h–1, respectively. By constructing an Arrhenius plot (ln kapp vs T–1) from the kapp values of the reactions performed in acetone, apparent energy of activation of 32 kJ mol–1 was obtained. For the noncatalyzed polycondensation of sebacic acid and glycerol in toluene at temperatures ranging from 120 to 140 °C, Maliger et al. (16) reported kapp values ranging from 0.04 to 0.13 h–1 and apparent energy of activation of 71 kJ mol–1. This indicates that CALB catalysis can increase the reaction rate of the polycondensation of sebacic acid and glycerol by approximately 5-fold and decrease the apparent energy of activation by approximately half, compared to the noncatalyzed polycondensation. The kapp of reactions performed in acetone increased by around 75% by increasing the temperature from 30 to 40 °C. However, a further temperature increase from 40 to 50 °C led to a minor increase in the kapp of just 25%. This tendency of the kapp to decrease in reactions performed in acetone, tetrahydrofuran, and acetonitrile by increasing the reaction temperature above 50–60 °C may be related to enzyme deactivation as discussed previously.

PGS Chain Growth and Branching

The temporal evolution of the number average degree of polymerization and average molar fraction of each glyceridic species (xi) in the reaction medium as a function of the time for the reactions performed in acetone at 30, 40, and 50 °C is presented in Figure 5a,b,c, respectively.

Figure 5

Figure 5. Number average degree of polymerization (Dpn, box solid) and the average molar fraction (xi) of glycerol (gray circle open) and glyceridic units 1T (maroon circle open), 2T (purple circle open), 1,3L (blue circle open), 1,2L (green circle open), and 1,2,3D (red circle open) in the reaction medium as a function of reaction time for reactions performed in acetone at (a) 30 °C, (b) 40 °C, and (c) 50 °C.

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The plots in Figure 5 show that the chain growth behavior of PGS is similar to that reported by Rao et al. (22) for poly(glycerol suberate) prepared by polycondensation of the diethyl suberate and glycerol via CALB catalysis, which is composed of three growth steps: (i) an initial linear growth step due to the reaction among terminal units to produce linear segments; (ii) graft growth, and (iii) dendritic growth occurring simultaneously through reactions between the terminal and linear units. The dendritic growth is characterized by a high steric hindrance that makes it difficult for the reactive groups in the middle of a polymeric chain to access the enzyme catalytic site. Therefore, the formation of 1,2,3D units probably proceeds toward the esterification of the primary hydroxyl available in the 1,2L unit. (22,67) However, as shown in Figure 5, the production of the 1,2,3D units occurs simultaneously to the consumption of the 1,3L units. This leads to the following question: Does the formation of 1,2,3D units proceed through the enzymatically catalyzed esterification of the secondary hydroxyl of 1,3L units or is it due to acyl migration, which converts 1,3L units into 1,2L units followed by the CALB-catalyzed esterification of the primary hydroxyl of 1,2L units, similar to the mechanism proposed by Lortie et al. (42) for the lipase-catalyzed synthesis of triolein?
Acyl migration is frequently observed in the synthesis of glycerides via enzymatic or chemical catalysts, and its suppression is a difficult task. (68,69) The rate of acyl migration depends on reaction parameters such as temperature, glyceride concentration, and solvent polarity, and it decreases with a decrease in solvent log P or temperature. (42,70−75) For glycerol-based polyesters prepared using a chemical catalyst that selectively esterifies primary hydroxyls, Slavko and Taylor (19) reported an increase in the 1,2L unit fraction and maintenance of the 1,2,3D unit fraction when polyesters mainly composed of 1,3L units were subjected to conditions favorable for the acyl migration reaction in the absence of the esterification catalyst. Many studies regarding acyl migration of glycerides show that at equilibrium, the molar ratio between monoglycerides esterified at primary hydroxyl and secondary hydroxyl is approximately 10, and the molar ratio for diglycerides with both primary hydroxyl esterified and with one primary and one secondary hydroxyl esterified is approximately 2. (42,68,70,75,77)Figure 6 presents these molar ratios as a function of time for PGS prepared in acetone at 30, 40, and 50 °C (data for other reaction conditions are presented in Figure S9).

Figure 6

Figure 6. Molar ratio of glyceridic units as a function of time for reactions performed in acetone at 30 °C (□), 40 °C (○), and 50 °C (Δ): (a) x1T/x2T and (b) x1,3L/x1,2L.

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Surprisingly, for all reaction conditions, the x1T/x2T and x1,3L/x1,2L ratios tend to values of around 10 and 2 at 24 h reaction, respectively. These values are reached at shorter reaction times as the temperature increases. By performing an experiment similar to that reported by Slavko and Taylor, (19) a solution of PGS with different DB in tetrahydrofuran in the presence of triethylamine and molecular sieves was prepared and maintained under gentle stirring for 24 h at 40 °C, in the absence of the esterification catalyst, to favor the acyl migration reaction. After this time, there was observed to be a tendency toward an increase in x1,2L, the maintenance of x1,2,3D, and the x1T/x2T and x1,3L/x1,2L ratios equal to 10 and 2, respectively (Table S7). The x1,3L/x1,2L ratio around 2 has also been observed for poly(glycerol suberate) and poly(oleic diacid-co-glycerol) prepared via CALB catalysis and for poly(oleic diacid-co-glycerol) prepared via metal catalysis. (22,29) The ratios x1T/x2T and x1,3L/x1,2L were very close for the polymers synthesized in different solvents at a given temperature (Figure S9), indicating that the acyl migration rate was not affected by the solvent. This tendency agrees with that observed by Duan et al. (37) and Li et al. (73) for the CALB-catalyzed esterification of glycerol and oleic acid in solvents with log P values that ranged from −0.24 to 4.7. In their study, it was reported that the reactions performed in polar solvents with log P < 1.0 have similar lower acyl migration constant rates and higher CALB selectivity toward glycerol primary hydroxyl compared to the use of apolar solvents with log P > 1.0.
Based on these results and the works of Rao et al. (22) and Lortie et al., (42) we propose a mechanism of the chain growth behavior and branching of glycerol-based polyesters prepared via CALB catalysis, Scheme 1.

Scheme 1

Scheme 1. Representation of the Mechanism of Glycerol-Based Polyester Chain Growth and Branching during the Simultaneous Occurrence of the CALB-Catalyzed Esterification and Acyl Migration (A.M.)
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The enzyme is mainly responsible for the esterification of glycerol primary hydroxyl groups to produce 1T and 1,3L units. The 2T and 1,2L units result mainly from acyl migration, and further esterification of 1,2L units by enzyme catalysis produces 1,2,3D units. The esterification of the primary hydroxyl of a 1,2L unit should be faster than the esterification of the secondary hydroxyl of a 1,3L unit, and the consumption of 1,2L units by esterification is compensated by acyl migration equilibrium, which restores 1,2L units from 1,3L units. Both reactions will proceed until the polymerization and acyl migration reactions achieve thermodynamic equilibrium and the molar fractions of each glyceridic unit reach a constant value with x1T/x2T = 10 and x1,3L/x1,2L = 2. The 2T unit molar fraction remains low and constant throughout the reaction, indicating a steady-state (Figure 5). Thus, the 2T unit formation rate and consuming rate in 1T and 1,2L due to acyl migration and CALB-catalyzed esterification, respectively, should be equivalent. Moreover, based on this mechanism, the CALB-catalyzed esterification is mainly responsible for the increase of the polymer degree of polymerization, whereas the acyl migration only changes the ester position from a primary to a secondary hydroxyl. Therefore, the kapp values describe mainly the CALB-catalyzed esterification reaction.
This set of results indicates that branching suppression is not possible for a polycondensation catalyzed by CALB under the reaction conditions investigated due to the occurrence of the acyl migration reaction. However, the PGS architecture, molecular weight, and degree of branching can be tailored by changing the reaction parameters such as the solvent, temperature, CALB amount, and sebacic acid/glycerol feed ratio, which are important strategies to tune the PGS elastomer properties.
The strategy to achieve linear polymers should be kinetic control using reaction conditions for which the esterification of primary hydroxyl and formation of 1T and 1,3L units are much faster than the rate of acyl migration. For example, this condition is probably achieved by the use of diarylborinic acid catalysts in which a catalyst–substrate adduct is formed, preventing the acyl migration reaction and the esterification of glycerol secondary hydroxyls, and the PGS formed is mostly composed of 1,3L units with less than 1% of the 1,2,3D unit. (19) The use of activated esters or bulk reactions for the CALB-catalyzed synthesis of glycerol-based polyester is other strategies that seem to delay acyl migration and allow the preparation of linear polymers with the higher molecular weight than achieved in the conditions studied here. However, after some time, acyl migration also seems to occur in these conditions and some degree of branching is observed as the polymer molecular weight increases. (29,31)

Conclusions

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The use of CALB as a catalyst for the polycondensation of glycerol and sebacic acid in low-hazard polar solvents and mild reaction conditions allows the preparation of PGS. These polyesters have pendant hydroxyl groups, low to relatively high molecular weight (Mw ranging from 3 to 16 kDa), and a degree of branching ranging from 24 to 42%. The influence of temperature on the polymerization is governed by good enzyme performance at temperatures up to 50 °C and enzyme denaturation at above 50 °C. The solvents seem to affect both polymer coil solvation and the enzyme structure and, consequently, the extent of the polymerization. However, the solvent does not seem to affect the acyl migration rate or CALB selectivity. The enzyme amount of 13.6 wt % leads to a higher PGS molecular weight for a 24 h reaction time, and by controlling the sebacic acid/glycerol feed ratio, it is possible to control the PGS architecture, molecular weight, degree of branching, and end-group functionality. Using acetone as a solvent at 40 °C, a higher rate constant (kapp = 1.5 h–1), a higher molecular weight (Mn = 9.4 kDa and Mw = 16 kDa), and a higher degree of branching (42%) were achieved for PGS. Therefore, the CALB-catalyzed synthesis of PGS is a suitable alternative to the conventional preparation of PGS. The kinetic study allowed us to understand polymer growth and branching. During the polycondensation reaction, CALB-catalyzed esterification and acyl migration occur simultaneously, and the latter is mainly responsible for the esterification of secondary hydroxyls and to give rise to branching.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.macromol.0c01709.

  • Summarized polycondensation conditions and characteristics of glycerol-based polyesters prepared via CALB catalysis, IR spectrum, 13C NMR spectrum, 1H–13C HSQC contour map, 1H–1H COSY contour map, temporal evolution of 1H NMR spectra signals, 1H NMR curve-fitted signals of methylene protons adjacent to the sebacic acid/ester carbonyl, structural parameters calculations, comparison of results from 1H NMR and quantitative 13C NMR, general data from the 1H NMR and GPC analyses, DLS analyses and CAC estimation, x1T/x2T and x1,3L/x1,2L molar fraction ratio as a function of time, and acyl migration experiment (PDF)

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Author Information

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  • Corresponding Author
  • Author
    • Giovanni B. Perin - Institute of Chemistry, University of Campinas, 13083-970 Campinas, SP, Brazil
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors would like to thank FAPESP (Process nos. 2018/01562-6 and 2015/25406–5), CNPq (Process no. 444392/2014-9), and Capes (Finance Code “001”) for the financial funding.

References

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    Biomacromolecules (2015), 16 (5), 1525-1533CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Poly(glycerol sebacate) (PGS) and its derivs. make up an attractive class of biomaterial owing to their tunable mech. properties with programmable biodegradability. In practice, however, the application of PGS is often hampered by frequent inconsistency in reproducing process conditions. The inconsistency stems from the volatile nature of glycerol during the esterification process. In this study, we suggest that the degree of esterification (DE) can be used to predict precisely the phys. status, the mech. properties, and the degrdn. of the PGS materials. Young's modulus is shown to linearly increase with DE, which is in agreement with an entropic spring theory of rubbers. To provide a processing guideline for researchers, we also provide a phys. status map as a function of curing temp. and time. The amt. of glycerol loss, obtainable by monitoring the evolution of the total mass loss and the DE during synthesis, is shown to make the predictions even more precise. We expect that these strategies can be applicable to different categories of polymers that involve condensation polymn. with the volatility of the reactants. In addn., we demonstrate that microwave-assisted prepolymn. is a time- and energy-efficient pathway to obtain PGS. For example, 15 min of microwave time is shown to be as efficient as prepolymn. in nitrogen atm. for 6 h at 130 °C. The quick synthesis method, however, causes a severe evapn. of glycerol, resulting in a large distortion in the monomer ratio between glycerol and sebacic acid. Consequently, more rigid PGS is produced under a similar curing condition compared to the conventional prepolymn. method. Finally, we demonstrate that the addn. of molecularly rigid crosslinking agents and network-structured inorg. nanoparticles are also effective in enhancing the mech. properties of the PGS-derived materials.
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  8. 8
    Barrett, D. G.; Yousaf, M. N. Design and applications of biodegradable polyester tissue scaffolds based on endogenous monomers found in human metabolism. Molecules 2009, 14, 4022– 4050,  DOI: 10.3390/molecules14104022
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    8
    Design and applications of biodegradable polyester tissue scaffolds based on endogenous monomers found in human metabolism
    Barrett, Devin G.; Yousaf, Muhammad N.
    Molecules (2009), 14 (10), 4022-4050CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)
    A review. Synthetic polyesters have deeply impacted various biomedical and engineering fields, such as tissue scaffolding and therapeutic delivery. Currently, many applications involving polyesters are being explored with polymers derived from monomers that are endogenous to the human metab. Examples of these monomers include glycerol, xylitol, sorbitol, and lactic, sebacic, citric, succinic, α-ketoglutaric, and fumaric acids. In terms of mech. versatility, crystallinity, hydrophobicity, and biocompatibility, polyesters synthesized partially or completely from these monomers can display a wide range of properties. The flexibility in these macromol. properties allows for materials to be tailored according to the needs of a particular application. Along with the presence of natural monomers that allows for a high probability of biocompatibility, there is also an added benefit that this class of polyesters is more environmentally friendly than many other materials used in biomedical engineering. While the selection of monomers may be limited by nature, these polymers have produced or have the potential to produce an enormous no. of successes in vitro and in vivo.
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  9. 9
    Wang, Y.; Kim, Y. M.; Langer, R. In vivo degradation characteristics of poly(glycerol sebacate). J. Biomed. Mater. Res., Part A 2003, 66A, 192– 197,  DOI: 10.1002/jbm.a.10534
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    9
    In vivo degradation characteristics of poly(glycerol sebacate)
    Wang, Yadong; Kim, Yu Mi; Langer, Robert
    Journal of Biomedical Materials Research, Part A (2003), 66A (1), 192-197CODEN: JBMRCH ISSN:. (John Wiley & Sons, Inc.)
    The authors have developed a series of biodegradable elastomers, poly(glycerol sebacate) (PGS), based on glycerol and sebacic acid. The polymers are potentially useful in soft tissue regeneration and engineering. To evaluate the performance of PGS in a physiol. environment, the authors compared their degrdn. profiles with poly(DL-lactide-co-glycolide) (50:50, carboxyl ended, Mw 15,000) in vivo. Among the parameters examd. are changes in wt. and mech. strength with time, implant geometry, surface characteristics, and degree of swelling. Unlike poly(DL-lactide-co-glycolide), PGS primarily degrades by surface erosion, which gives a linear degrdn. profile of mass, preservation of geometry and intact surface, and retention of mech. strength.
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  10. 10
    Cai, W.; Liu, L. Shape-memory effect of poly(glycerol – sebacate) elastomer. Mater. Lett. 2008, 62, 2171– 2173,  DOI: 10.1016/j.matlet.2007.11.042
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    There is no corresponding record for this reference.
  11. 11
    Mortensen, P. B. C6-C10-dicarboxylic aciduria in starved, fat-fed and diabetic rats receiving decanoic acid or medium-chain triacylglycerol. An in vivo measure of the rate of beta-oxidation of fatty acids. Biochim. Biophys. Acta, Lipids Lipid Metab. 1981, 664, 349– 355,  DOI: 10.1016/0005-2760(81)90057-6
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    11
    C6-C10-dicarboxylic aciduria in starved, fat-fed and diabetic rats receiving decanoic acid or medium-chain triacylglycerol. An in vivo measure of the rate of β-oxidation of fatty acids
    Mortensen, Per Broebech
    Biochimica et Biophysica Acta, Lipids and Lipid Metabolism (1981), 664 (2), 349-55CODEN: BBLLA6; ISSN:0005-2760.
    Administration of decanoic acid to rats resulted not only in elevated urinary excretions of the C10-dicarboxylic acid (sebacic acid), but also in highly elevated excretions of the β-oxidn. products C8- and C6-dicarboxylic acids (suberic and adipic acids). Activation of the lipid metab. by starvation, fat-feeding, and exptl. diabetes increased the excretions of adipic acid and decreased the excretions of sebacic acid, i.e. the rate of oxidn. of fatty acids was correlated with the adipic:sebacic acid ratio in urine. Compared with nondiabetic unstarved rats, the adipic:sebacic acid ratio was elevated 2-3-, 8-16-, 5-19-, and 22-88-fold in rats which were, resp., starved for 2 days, starved for 4 days, on a fat-free diet for 4 days, and ketotic due to streptozotocin-induced diabetes. All rats with ratios >10 were ketotic (urinary excretions of 3-hydroxybutyric acid >500 μg/mg creatinine) and all rats with ratios <4 were nonketotic; ketosis was a variable finding in rats with intermediary ratios. Similar changes in the ratio of excreted dicarboxylic acids were found when medium-chain triacylglycerols were fed instead of decanoic acid.
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  12. 12
    Liu, G.; Hinch, B.; Beavis, A. D. Mechanisms for the Transport of α,ω-Dicarboxylates through the Mitochondrial Inner Membrane. J. Biol. Chem. 1996, 271, 25338– 25344,  DOI: 10.1074/jbc.271.41.25338
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    12
    Mechanisms for the transport of α,ω-dicarboxylates through the mitochondrial inner membrane
    Liu, Guoying; Hinch, Bryan; Beavis, Andrew D.
    Journal of Biological Chemistry (1996), 271 (41), 25338-25344CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    α,ω-Dicarboxylates have antibacterial properties, have been used in the treatment of hyperpigmentary disorders, are active against various melanoma cell lines, and can also undergo β-oxidn. Little, however, is known about their transport. In this paper, we examine the mitochondrial transport of α,ω-dicarboxylates ranging from oxalate (DC2) to sebacate (DC10). DC2-DC10 are transported by the inner membrane anion channel (IMAC). DC6-DC10 are also transported by an electroneutral mechanism that appears to reflect transport of the acid through the lipid bilayer. AT 37°C and pH 7.0, DC10 is transported very rapidly at 3 μmol/min·mg, and respiring mitochondria swell in the K+ salts of these acids. This transport mechanism is probably the major pathway by which the longer dicarboxylates enter cells, bacteria, and mitochondria. We also demonstrate that DC5-DC10 can also be transported by an electroneutral mechanism mediated by tributyltin, a potent inhibitor of IMAC. The mechanism appears to involve electroneutral exchange of a TBT-dicarboxylate-H complex for TBT-OH. Finally, we present evidence that of all the dicarboxylates tested only DC2-DC4 can be transported by the classical dicarboxylate carrier.
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  13. 13
    Sundback, C. A.; Shyu, J. Y.; Wang, Y.; Faquin, W.; Langer, R. S.; Vacanti, J. P.; Hadlock, T. A. Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material. Biomaterials 2005, 26, 5454– 5464,  DOI: 10.1016/j.biomaterials.2005.02.004
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    13
    Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material
    Sundback, Cathryn A.; Shyu, Jeffery Y.; Wang, Yadong; Faquin, William C.; Langer, Robert S.; Vacanti, Joseph P.; Hadlock, Tessa A.
    Biomaterials (2005), 26 (27), 5454-5464CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    No satisfactory method currently exists for bridging neural defects. Autografts lead to inadequate functional recovery, and most available artificial neural conduits possess unfavorable swelling and pro-inflammatory characteristics. This study examd. the biocompatibility of a novel biodegradable elastomer, poly(glycerol sebacate) (PGS), for neural reconstruction applications, as the material possesses favorable mech. property and degrdn. characteristics. The effect of PGS on Schwann cell metabolic activity, attachment, proliferation, and apoptosis were examd. in vitro in comparison with poly(lactide-co-glycolide) (PLGA), a biomaterial widely utilized for tissue engineering applications. The in vivo tissue response to PGS was compared with PLGA implanted juxtaposed to the sciatic nerve; the phys. changes in the implant material were measured during the degrdn. process. PGS had no deleterious effect on Schwann cell metabolic activity, attachment, or proliferation, and did not induce apoptosis; the in vitro effects of PGS were similar to or superior to that of PLGA. In vivo, PGS demonstrated a favorable tissue response profile compared with PLGA, with significantly less inflammation and fibrosis and without detectable swelling during degrdn. PGS is an excellent candidate material for neural reconstruction applications given its lack of in vitro Schwann cell toxicity and minimal in vivo tissue response.
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  14. 14
    Lau, C. C.; Bayazit, M. K.; Knowles, J. C.; Tang, J. Tailoring degree of esterification and branching of poly(glycerol sebacate) by energy efficient microwave irradiation. Polym. Chem. 2017, 8, 3937– 3947,  DOI: 10.1039/C7PY00862G
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    14
    Tailoring degree of esterification and branching of poly(glycerol sebacate) by energy efficient microwave irradiation
    Lau, Chi Ching; Bayazit, Mustafa Kemal; Knowles, Jonathan Campbell; Tang, Junwang
    Polymer Chemistry (2017), 8 (26), 3937-3947CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    Poly(glycerol sebacate) (PGS) is known as an exciting biomaterial owing to its tunable mech. properties and controllable degrdn. rate. However, it is always challenging to control these properties. In this study, we have proposed a solvent-based system to provide a better control of reaction temp. in a microwave cavity, which can minimize evapn. of monomers, and water was collected to analyze the degree of esterification. Pre-PGSs with varied degrees of esterification were prepd. using both single mode and multimode microwave cavity irradn. (MI) in this solvent-based reaction system. For a similar degree of esterification of pre-PGSs, the reaction time was almost halved with a better control on mech. properties by single mode MI compared to multimode MI. Furthermore, the single mode MI approach was compared with the conventional heating (CH) approach. The mech. properties and degrdn. rate of PGSs can be controlled readily by using the single mode MI approach compared to CH, which are crucial for their application as a biomaterial. It has been found that the single mode MI not only accelerates the pre-polymn. process rate by six times, but also speeds up the curing time to the same extent. The Young's modulus of PGSs prepd. by single mode MI is increased from 0.77 to 3.14 MPa when the degree of esterification is 66.82%, which is 50% higher than that reported in the literature. Furthermore, PGS using a highly branched pre-PGS prepd. by the single mode MI method has a large degree of flexibility. It can achieve a much higher Young's modulus than that obtained by CH with a short curing time (<10 h). In addn., the residual mass of PGSs prepd. by single mode MI is varied from 78.54% to 92.96% compared to the CH method that ranges from 84.24% to 93.31%. Thus, these highly branched PGSs produced by single mode MI also show a wider degrdn. window (approx. 59% higher degree of flexibility than the CH method), which is found to be highly dependent on the degree of esterification and curing time of the pre-polymer, and controlled by branching.
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  15. 15
    Conejero-garcía, Á.; Gimeno, H. R.; Sáez, Y. M.; Vilariño-feltrer, G.; Ortuño-lizarán, I.; Vallés-lluch, A. Correlating synthesis parameters with physicochemical properties of poly(glycerol sebacate). Eur. Polym. J. 2017, 87, 406– 419,  DOI: 10.1016/j.eurpolymj.2017.01.001
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    15
    Correlating synthesis parameters with physicochemical properties of poly(glycerol sebacate)
    Conejero-Garcia, Alvaro; Gimeno, Hector Rivero; Saez, Yolanda Moreno; Vilarino-Feltrer, Guillermo; Ortuno-Lizaran, Isabel; Valles-Lluch, Ana
    European Polymer Journal (2017), 87 (), 406-419CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)
    Poly(glycerol sebacate), PGS, is an elastomeric biodegradable polyester increasingly proposed in a variety of biomedical applications. It is prepd. by polycondensation of sebacic acid and glycerol in a first stage in which a prepolymer is obtained, followed by a curing to conveniently crosslink it. In this work, synthesis parameters such as the curing temp. and time, and the molar ratio between reactants, were systematically varied to correlate them with the physicochem. properties of the resulting polymer networks. The efficiency of each manufg. process was quantified through the relative mass effectively crosslinked and insol. in THF. IR spectra gave an estn. of the ratio of non-condensed polar terminal groups. These results were correlated with swelling results, which in turn provided the means to calc. the chains d. through Flory-Rehner equil. swelling equation for lightly crosslinked polymers. The role of the synthesis parameters on the phys. state of the resulting polymers, as well as their proneness to hydrolyze, were followed. The results obtained highlight the relevance of rinsing them following synthesis, to remove non-crosslinked chains that easily diffuse to the surrounding medium. Curing under mild conditions equimolar mixts. of sebacic acid and glycerol proved to lead to poorly crosslinked swellable networks, which hydrolyze easily in bulk mode. Alternative molar ratios yield sticky and difficult to handle materials at higher polyol fractions in the reactive mixt., while an excess of acid terminal groups leads to a faster mass loss by hydrolysis in aq. media together with surface salts deposition, concomitant with a lesser cell viability in in vitro culture. PGS synthesized from an equimolar ratio between reactants and cured at 130 °C or higher, for 48 h or longer, show suitable features for their use in tissue engineering applications where hydrophobic surface-degradable rubbers are required, without significant differences among them.
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  16. 16
    Maliger, R.; Halley, P. J.; Cooper-White, J. J. Poly(glycerol-sebacate) bioelastomers-kinetics of step-growth reactions using Fourier Transform (FT)-Raman spectroscopy. J. Appl. Polym. Sci. 2013, 127, 3980– 3986,  DOI: 10.1002/app.37719
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    16
    Poly(glycerol-sebacate) bioelastomers-kinetics of step-growth reactions using Fourier Transform (FT)-Raman spectroscopy
    Maliger, Raju; Halley, Peter J.; Cooper-White, Justin J.
    Journal of Applied Polymer Science (2013), 127 (5), 3980-3986CODEN: JAPNAB; ISSN:0021-8995. (John Wiley & Sons, Inc.)
    Kinetic studies of the esterification of glycerol (G) and sebacic acid (SA) at three molar ratios (0.6, 0.8, 1.0) and at three temps. (120, 130, 140°C) to form poly(glycerol-sebacate) were performed and assessed using FT-Raman spectroscopy. The quant. changes in the concns. of carboxylic acid and ester groups within the forming bioelastomer were measured and the chem. rate consts. (k) detd. from the kinetic scheme were first-order, with respect to sebacic acid concn. Increasing the reaction temp. by 20°C is noted to increase the chem. rate const. (k) by a factor of up to 4.5 and the total extent of conversion at early times for the molar ratios investigated. The activation energy (Ea) and the pre-exponential factor (A0) for these three stoichiometric ratios were calcd., which varied in accordance with the av. functionality of the system. Under isothermal conditions, the chem. rate const. remained unchanged with an increase in the extent of the reaction (α) until a spontaneous transition resulted in the shift in the mechanism from kinetics to diffusion controlled. The Young's moduli of the PGS polymers were found to depend primarily on the av. functionality of the system and the curing period. This investigation confirms the reaction mechanism for PGS polymer synthesis and shows the flexibility afforded to PGS properties and reaction times through varying the stoichiometric ratios of glycerol to sebacic acid. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2012.
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    You, Z.; Cao, H.; Gao, J.; Shin, P. H.; Day, B. W.; Wang, Y. A functionalizable polyester with free hydroxyl groups and tunable physiochemical and biological properties. Biomaterials 2010, 31, 3129– 3138,  DOI: 10.1016/j.biomaterials.2010.01.023
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    17
    A functionalizable polyester with free hydroxyl groups and tunable physiochemical and biological properties
    You, Zhengwei; Cao, Haiping; Gao, Jin; Shin, Paul H.; Day, Billy W.; Wang, Yadong
    Biomaterials (2010), 31 (12), 3129-3138CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Polyesters with free functional groups allow facile modifications with biomols., which can lead to versatile biomaterials that afford controlled interactions with cells and tissues. Efficient synthesis of functionalizable polyesters (Functionalizable polymer is defined as a polymer with functional groups that readily react with biomols. and functionalized biomaterial as one already modified with biomols.) is still a challenge that greatly limits the availability and widespread applications of biofunctionalized synthetic polymers. Here we report a simple route to prep. a functionalizable polyester, poly(sebacoyl diglyceride) (PSeD) bearing free hydroxyl groups. The key synthetic step is an epoxide ring-opening polymn., instead of the traditional polycondensation that produces poly(glycerol sebacate) (PGS). PSeD has a more defined structure with mostly linear backbone, more free hydroxyl groups, higher mol. wt., and lower polydispersity than PGS. Crosslinking PSeD with sebacic acid yields a polymer five times tougher and more elastic than cured PGS. PSeD exhibits good cytocompatibility in vitro. Furthermore, functionalization by glycine proceeds with high efficiency. This versatile synthetic platform can offer a large family of biodegradable, functionalized polymers with tunable physiochem. and biol. properties useful for a wide range of biomedical applications.
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  18. 18
    You, Z.; Bi, X.; Wang, Y. Fine Control of Polyester Properties via Epoxide ROP Using Monomers Carrying Diverse Functional Groups. Macromol. Biosci. 2012, 12, 822– 829,  DOI: 10.1002/mabi.201200035
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    18
    Fine Control of Polyester Properties via Epoxide ROP Using Monomers Carrying Diverse Functional Groups
    You, Zhengwei; Bi, Xiaoping; Wang, Yadong
    Macromolecular Bioscience (2012), 12 (6), 822-829CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Synthetic biodegradable polymers are important biomaterials. However, most of them are biol. inert. Free functional groups can allow easy biofunctionalization. Efficient introduction of functional groups to biodegradable polymers is still a challenge. Here, a practical strategy is presented to synthesize various functional polyesters with free hydroxyl groups polymd. via epoxide ring-opening polymn. (ROP) between dicarboxylic acids and diglycidyl dicarboxylates without protection and deprotection. The polymers exhibit a wide range of phys., thermal, and mech. properties, and good cytocompatibilities. This synthetic platform is expected to lead to functional polymers useful for a wide variety of biomedical applications.
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    Slavko, E.; Taylor, M. S. Catalyst-controlled polycondensation of glycerol with diacyl chlorides: Linear polyesters from a trifunctional monomer. Chem. Sci. 2017, 8, 7106– 7111,  DOI: 10.1039/C7SC01886J
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    19
    Catalyst-controlled polycondensation of glycerol with diacyl chlorides: linear polyesters from a trifunctional monomer
    Slavko, Ekaterina; Taylor, Mark S.
    Chemical Science (2017), 8 (10), 7106-7111CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    Diarylborinic acids catalyze the formation of linear polyesters from glycerol, a trifunctional, carbohydrate-based monomer. The selective activation of 1,2-diols over isolated alcs. by the organoboron catalyst results in polymers that are essentially free of branching or crosslinking and possess a high fraction of 1,3-enchained glycerol units, as assessed by 1H and 13C NMR spectroscopy. The ability to generate well-defined polyester architectures from glycerol is significant in light of the numerous applications of such macromols., particularly in the biomedical area. Isomerization, post-polymn. functionalization and controlled crosslinking reactions of the obtained linear poly(glycerol esters) are demonstrated.
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    Kline, B. J.; Beckman, E. J.; Russell, A. J. One-step biocatalytic synthesis of linear polyesters with pendant hydroxyl groups. J. Am. Chem. Soc. 1998, 120, 9475– 9480,  DOI: 10.1021/ja9808907
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    20
    One-Step Biocatalytic Synthesis of Linear Polyesters with Pendant Hydroxyl Groups
    Kline, Billie J.; Beckman, Eric J.; Russell, Alan J.
    Journal of the American Chemical Society (1998), 120 (37), 9475-9480CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The chem. synthesis of linear polyesters with various hydrophilic functional groups is difficult, involving a multistep reaction pathway and synthesis of a suitable monomer with a protected functional group. A straightforward conventional synthesis from a trifunctional compd., such as glycerol, and a diester or dicarboxylic acid to produce a polyester results in the formation of networks. An alternative approach to the one-step synthesis of aliph. hydroxyl-substituted polyesters from divinyl adipate (DVA) and various triols has been found by utilizing the intrinsic specificity of an enzyme. The wt. av. mol. wts. of the resulting polyesters vary according to the triol used and range from ∼3,000 to 14,000 Da. Anal. by MALDI-TOF mass spectrometry has confirmed the presence of a linear polyester with hydroxyl substituents, and there is no evidence for network formation. The pendant groups are 90-95% secondary and 5-10% primary hydroxyl groups. Exptl. detn. of hydroxyl no. verifies that one hydroxyl group is present on each repeat unit of the substituted polyester. By the addn. of increasing amts. of 1,4-butanediol to the reaction mixt. of glycerol and DVA, predictable and sensitive control of the hydroxyl no. can be accomplished.
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    Iglesias, L. E.; Fukuyama, Y.; Nonami, H.; Erra-Balsells, R.; Baldessari, A. A simple enzymatic procedure for the synthesis of a hydroxylated polyester from glycerol and adipic acid. Biotechnol. Tech. 1999, 13, 923– 926,  DOI: 10.1023/A:1008958212814
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    21
    A simple enzymatic procedure for the synthesis of a hydroxylated polyester from glycerol and adipic acid
    Iglesias, Luis E.; Fukuyama, Yuko; Nonami, Hiroshi; Erra-Balsells, Rosa; Baldessari, Alicia
    Biotechnology Techniques (1999), 13 (12), 923-926CODEN: BTECE6; ISSN:0951-208X. (Kluwer Academic Publishers)
    Lipase B from Candida antarctica regioselectively catalyzed the polyesterification of glycerol with adipic acid. UV-MALDI-TOF-MS anal. of the polymers shows low mol. wt. polyesters (1314-1716) with very narrow polydispersities (1.0-1.2).
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    Rao, Z. K.; Ni, H. L.; Li, Y.; Zhu, H. Y.; Liu, Y.; Hao, J. Y. Macroscopic Scaffold Control for Lipase-Catalyzed Dendritic Polyol-Polyesters. Macromol. Chem. Phys. 2019, 220, 1900048  DOI: 10.1002/macp.201900048
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    Zeng, F.; Yang, X.; Li, D.; Dai, L.; Zhang, X.; Lv, Y.; Wei, Z. Functionalized polyesters derived from glycerol: Selective polycondensation methods toward glycerol-based polyesters by different catalysts. J. Appl. Polym. Sci. 2019, 48574  DOI: 10.1002/app.48574
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    Uyama, H.; Inada, K.; Kobayashi, S. Regioselective polymerization of divinyl sebacate and triols using lipase catalyst. Macromol. Rapid. Commun. 1999, 20, 171– 174,  DOI: 10.1002/(SICI)1521-3927(19990401)20:4<171::AID-MARC171>3.0.CO;2-2
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    24
    Regioselective polymerization of divinyl sebacate and triols using lipase catalyst
    Uyama, Hiroshi; Inada, Kojiro; Kobayashi, Shiro
    Macromolecular Rapid Communications (1999), 20 (4), 171-174CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH)
    The lipase-catalyzed regioselective polymn. of divinyl sebacate and triols was carried out. Immobilized lipase derived from Candida antarctica induces the polymn. of divinyl sebacate and glycerol, yielding a sol. polymer of relatively high mol. wt. NMR anal. showed that 1,3-diglyceride is a main unit and the branching unit (triglyceride) is contained in the resulting polymer. These data indicate that the polymn. proceeds regioselectively to give the reactive polyester having a pendant OH group.
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    Uyama, H.; Inada, K.; Kobayashi, S. Regioselectivity Control in Lipase-Catalyzed Polymerization of Divinyl Sebacate and Triols. Macromol. Biosci. 2001, 1, 40– 44,  DOI: 10.1002/1616-5195(200101)1:1<40::AID-MABI40>3.0.CO;2-T
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    25
    Regioselectivity control in lipase-catalyzed polymerization of divinyl sebacate and triols
    Uyama, Hiroshi; Inada, Kojiro; Kobayashi, Shiro
    Macromolecular Bioscience (2001), 1 (1), 40-44CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH)
    The polymn. of divinyl sebacate and 3 different triols (glycerol, 1,2,4-butanetriol, and 1,2,6-hexanetriol) in presence of lipase catalyst was studied by variation of reaction parameters (i.e., temp. and feed ratio of monomers) as well as enzyme origin (i.e., lipases derived from Candida antarctica, Muco miehei, and Pseudomonas cepacia). The resulting polymers were examd. by size exclusion chromatog. and various 13C NMR techniques (microstructure). By proper selection of conditions, regiospecific polymn. at the α,ω-position of the triol was achieved, yielding a linear polymer having a reactive OH-group in the main chain.
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    Kumar, A.; Kulshrestha, A. S.; Gao, W.; Gross, R. A. Versatile Route to Polyol Polyesters by Lipase Catalysis. Macromolecules 2003, 36, 8219– 8221,  DOI: 10.1021/ma0351827
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    Versatile Route to Polyol Polyesters by Lipase Catalysis
    Kumar, Ajay; Kulshrestha, Ankur S.; Gao, Wei; Gross, Richard A.
    Macromolecules (2003), 36 (22), 8219-8221CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    A simple and versatile strategy to perform regioselective lipase-catalyzed condensation polymns. between diacids and reduced sugar polyols is described. Sorbitol and glycerol were reacted with adipic acid under Novozyme-435 catalysis in absence and presence of 1,8-octanediol to produce related polyol terpolyesters rich in OH functionality. Soly., thermal stability, melting transitions, and crystallinity of the polyol terpolyesters were studied.
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    Kulshrestha, A. S.; Gao, W.; Gross, R. A. Glycerol copolyesters: Control of branching and molecular weight using a lipase catalyst. Macromolecules 2005, 38, 3193– 3204,  DOI: 10.1021/ma0480190
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    Glycerol Copolyesters: Control of Branching and Molecular Weight Using a Lipase Catalyst
    Kulshrestha, Ankur S.; Gao, Wei; Gross, Richard A.
    Macromolecules (2005), 38 (8), 3193-3204CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Immobilized Lipase B from Candida antartica (Novozyme 435) catalyzed bulk polycondensations at 70 °C for 42 h that resulted in hyperbranched polyesters with octanediol-adipate and glycerol-adipate repeat units. Instead of using org. solvents, the monomers adipic acid (A2), 1,8-octanediol (B2), and glycerol (B'B2) were combined to form monophasic ternary mixts. During the first 18 h of a copolymn. with monomer feed ratio (A2 to B2 to B'B2) 1.0:0.8:0.2 mol/mol, the regioselectivity of Novozyme 435 resulted in linear copolyesters. Extending the reaction to 42 h gave hyperbranched copolymers with dendritic glycerol units. The % regioselectivity for esterifications at the primary glycerol positions ranged from 77 to 82% and was independent of glycerol content in the monomer feed. Variation of glycerol in the monomer feed gave copolymers with degree of branching (DB) from 9 to 58%. In one example, a hyperbranched copolyester with 18 mol % glycerol-adipate units was formed in 90% yield, with Mw 75 600 (by SEC-MALLS), Mw/Mn 3.1, and DB 19%. Generalized structures were created to depict that for hyperbranched glycerol copolyesters and the progression of products formed at reaction times from 5 min to 42 h.
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    Kallinteri, P.; Higgins, S.; Hutcheon, G. A.; St. Pourçain, C. B.; Garnett, M. C. Novel functionalized biodegradable polymers for nanoparticle drug delivery systems. Biomacromolecules 2005, 6, 1885– 1894,  DOI: 10.1021/bm049200j
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    Novel Functionalized Biodegradable Polymers for Nanoparticle Drug Delivery Systems
    Kallinteri, Paraskevi; Higgins, Sean; Hutcheon, Gillian A.; St. Pourcain, Christopher B.; Garnett, Martin C.
    Biomacromolecules (2005), 6 (4), 1885-1894CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    We have prepd. and screened a library of novel functionalized polymers for development of nanoparticle drug delivery systems. The polymer backbone consisting of two ester-linked, non-toxic, biol. monomers, glycerol and adipic acid, was prepd. using a hydrolytic enzyme. The specificity of the chosen enzyme yields a linear polymer with one free pendant hydroxyl group per repeat unit, which can be further functionalized. This protocol gives control over the backbone polymer mol. wt., together with the ability to incorporate various amts. of different fatty acyl substituents. These functionalized polymers are able to self-assemble into well-defined small particles of high homogeneity with a very low toxicity. They are able to incorporate a water sol. drug, dexamethasone phosphate, with a high efficiency and drug loading which varies with the polymer specification. The above characteristics strongly suggest that these polymers could be developed into useful nanoparticulate drug delivery systems.
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    Yang, Y.; Lu, W.; Cai, J.; Hou, Y.; Ouyang, S.; Xie, W.; Gross, R. A. Poly(oleic diacid-co-glycerol): Comparison of polymer structure resulting from chemical and lipase catalysis. Macromolecules 2011, 44, 1977– 1985,  DOI: 10.1021/ma102939k
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    Poly(oleic diacid-co-glycerol): comparison of polymer structure resulting from chemical and lipase catalysis
    Yang, Yixin; Lu, Wenhua; Cai, Jiali; Hou, Yu; Ouyang, Suyang; Xie, Wenchun; Gross, Richard A.
    Macromolecules (Washington, DC, United States) (2011), 44 (7), 1977-1985CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    This study compares the synthesis and structure of poly(oleic diacid-co-glycerol) that results by using immobilized Candida antarctica Lipase B (Novozym 435, N435) and di-Bu tin oxide (DBTO) as catalysts. By using N435 catalysis and an oleic diacid to glycerol molar ratio of 1.0:1.0, the resulting polyester no.-av. mol. wts. (Mn) were 6000 g/mol at 6 h and 9100 g/mol at 24 h with low branching degree (Den% of glycerol 13%-16%). 13C NMR spectra of these polyesters revealed their chain-ends consist exclusively of monosubstituted glycerol units. Further diversification in polymer structure was achieved by using N435 catalysis and by changing the feed ratio of oleic diacid to glycerol from 1.0:1.0 to 1.5:1.0 in 0.1 increments. Resulting polyesters were not crosslinked (no obsd. gel fraction), had similar Mn values (generally between 4800 and 6000 g/mol), but differed in dendritic unit content, glycerol unit degree of substitution, and end-group structure (monosubstituted glyercol vs. carboxyl end-groups). In contrast, by using DBTO as catalyst and an oleic diacid to glycerol molar ratio of 1.0:1.0, polyester Mn of 1700 g/mol was obtained at 6 h and, thereafter, a gel was formed due to crosslinking. As a consequence of N435's ability to deter crosslink reactions owing to steric hindrance at the active site, a family of unique, sol., hyperbranched copolyesters was formed.
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    Naolou, T.; Weiss, V. M.; Conrad, D.; Busse, K.; Mäder, K.; Kressler, J. Fatty Acid Modified Poly(glycerol adipate) - Polymeric Analogues of Glycerides. In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C.; Kressler, J., Eds.; ACS Symposium Series; American Chemical Society: Washington, 2013; Chapter 4, pp 39– 52.
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    Taresco, V.; Creasey, R. G.; Kennon, J.; Mantovani, G.; Alexander, C.; Burley, J. C.; Garnett, M. C. Variation in structure and properties of poly(glycerol adipate) via control of chain branching during enzymatic synthesis. Polymer 2016, 89, 41– 49,  DOI: 10.1016/j.polymer.2016.02.036
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    Variation in structure and properties of poly(glycerol adipate) via control of chain branching during enzymatic synthesis
    Taresco, V.; Creasey, R. G.; Kennon, J.; Mantovani, G.; Alexander, C.; Burley, J. C.; Garnett, M. C.
    Polymer (2016), 89 (), 41-49CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)
    Poly (glycerol adipate) (PGA) can be produced from divinyl adipate and unprotected glycerol by an enzymic route to generate a polymer with relatively low molar mass (12 kDa). PGA bears a pendant hydroxyl group which imparts a hydrophilic character to this water insol. polymer. We have examd. the effect of synthesis temp. on polymer characteristics through various techniques including FT-IR, 1H and 13C NMR, surface and thermal anal., both to expand the data already present in the literature about this material and to understand better its properties for potential pharmaceutical applications. The use of a lipase (Novozym 435) as a catalyst suppresses crosslinking at the pendant glyceryl hydroxyl through steric hindrance at the active site, thus producing polymers with low degrees of branching (5-30%), and removes the need for any pre- or post-polymn. protection/deprotection reactions. Careful temp. control during synthesis can give polymers with reproducible mol. wts. and reduced amts. of polymer branching compared to synthesis at higher temps. Due to the ability of the synthetic route to produce a range of structures, PGA generated by enzymic routes may emerge as a useful biodegradable polymer platform to engineer solid dispersions or nanoparticles for healthcare applications.
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    Valerio, O.; Misra, M.; Mohanty, A. K. Poly(glycerol-co-diacids) Polyesters: From Glycerol Biorefinery to Sustainable Engineering Applications, A Review. ACS Sustainable Chem. Eng. 2018, 6, 5681– 5693,  DOI: 10.1021/acssuschemeng.7b04837
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    Poly(glycerol-co-diacids) Polyesters: From Glycerol Biorefinery to Sustainable Engineering Applications, A Review
    Valerio, Oscar; Misra, Manjusri; Mohanty, Amar K.
    ACS Sustainable Chemistry & Engineering (2018), 6 (5), 5681-5693CODEN: ASCECG; ISSN:2168-0485. (American Chemical Society)
    A review. Upgrading of biobased glycerol to com. products is a necessary step on sustainable development of oleaginous biomass biorefining. The synthesis of poly(glycerol-co-diacid) polyester materials is an attractive option for glycerol usage that can produce a wide range of products of com. interest. These polymeric materials could be used on industrial applications as biomedical devices, surfactants and in thermoplastic material development. In this review, the process engineering aspects leading to tailorable polymeric products are comprehensively analyzed with emphasis on control of mol. architecture and functionality. Mol. wt., degree of branching, mech. properties and surface chem. of the materials can be controlled by fine tuning synthesis procedures to match custom specifications in end products. Potential usage of poly(glycerol-co-diacid) materials with tailored physicochem. properties on industrially relevant applications is presented. Advantages and challenges in the synthesis of these novel polymeric materials for value added application are addressed and discussed.
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    Ortiz, C.; Ferreira, M. L.; Barbosa, O.; dos Santos, J. C. S.; Rodrigues, R. C.; Berenguer-Murcia, Á.; Briand, L. E.; Fernandez-Lafuente, R. Novozym 435: The ‘perfect’ lipase immobilized biocatalyst?. Catal. Sci. Technol. 2019, 9, 2380– 2420,  DOI: 10.1039/C9CY00415G
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    Novozym 435: the "perfect" lipase immobilized biocatalyst?
    Ortiz, Claudia; Ferreira, Maria Lujan; Barbosa, Oveimar; dos Santos, Jose C. S.; Rodrigues, Rafael C.; Berenguer-Murcia, Angel; Briand, Laura E.; Fernandez-Lafuente, Roberto
    Catalysis Science & Technology (2019), 9 (10), 2380-2420CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
    A review. Novozym 435 (N435) is a com. available immobilized lipase produced by Novozymes. It is based on immobilization via interfacial activation of lipase B from Candida antarctica on a resin, Lewatit VP OC 1600. This resin is a macroporous support formed by poly(Me methacrylate) crosslinked with divinylbenzene. N435 is perhaps the most widely used com. biocatalyst in both academy and industry. Here, we review some of the success stories of N435 (in chem., energy and lipid manipulation), but we focus on some of the problems that the use of this biocatalyst may generate. Some of these problems are just based on the mechanism of immobilization (interfacial activation) that may facilitate enzyme desorption under certain conditions. Other problems are specific to the support: mech. fragility, moderate hydrophilicity that permits the accumulation of hydrophilic compds. (e.g., water or glycerin) and the most crit. one, support dissoln. in some org. media. Finally, some solns. (N435 coating with silicone, enzyme phys. or chem. crosslinking, and use of alternative supports) are proposed. However, the N435 history, even with these problems, may continue in the coming future due to its very good properties if some simpler alternative biocatalysts are not developed.
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    Yoon, K. R.; Hong, S. P.; Kong, B.; Choi, I. S. Polycondensation of sebacic acid with primary and secondary hydroxyl groups containing diols catalyzed by Candida antarctica lipase B. Synth. Commun. 2012, 42, 3504– 3512,  DOI: 10.1080/00397911.2011.585267
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    Polycondensation of Sebacic Acid with Primary and Secondary Hydroxyl Groups Containing Diols Catalyzed by Candida antarctica Lipase B
    Yoon, Kuk Ro; Hong, Suk-Pyo; Kong, Bokyung; Choi, Insung S.
    Synthetic Communications (2012), 42 (23), 3504-3512CODEN: SYNCAV; ISSN:0039-7911. (Taylor & Francis, Inc.)
    The aliph. polyesters are normally synthesized by ester interchange reactions or direct esterification of hydroxyacids or diacid/diol combinations. Biotransformation, utilizing the enzymes as catalysts, was accepted as an alternative route for the synthesis of aliph. polyesters and offers various advantages compared with the conventional, metal-catalyzed polymn. reactions. Previous studies indicated that lipase-catalyzed polycondensation reactions between diols and diacids occurred preferentially at primary hydroxyl groups of diols, when diols contained both primary and secondary hydroxyl groups. In this work, we investigated lipase-catalyzed polycondensation of diacids and secondary hydroxyl group-contg. diols, and successfully synthesized polyesters by polycondensation with secondary hydroxyl groups as well as primary hydroxyl groups. Various diols, glycerol, 1,2-propanediol, 1,3-butanediol, 2,3-butanediol, and 2,4-pentanediol were tested for the polycondensation. The polymn. was achieved by heating a mixt. of lipase B, sebacic acid, and the diols in anhyd. toluene at 100 °C for 72 h. The resulting polymers were characterized by 1H and 13C NMR spectroscopy, Fourier transform-IR spectroscopy, thermogravimetric anal., and gel permeation chromatog.
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    Cha, H. J.; Park, J. B.; Park, S. Esterification of Secondary Alcohols and Multi-hydroxyl Compounds by Candida antarctica Lipase B and Subtilisin. Biotechnol. Bioprocess. Eng. 2019, 24, 41– 47,  DOI: 10.1007/s12257-018-0379-1
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    Esterification of Secondary Alcohols and Multi-hydroxyl Compounds by Candida antarctica Lipase B and Subtilisin
    Cha, Hee-Jeong; Park, Jin-Byung; Park, Seongsoon
    Biotechnology and Bioprocess Engineering (2019), 24 (1), 41-47CODEN: BBEIAU; ISSN:1226-8372. (Korean Society for Biotechnology and Bioengineering)
    Enzyme-catalyzed esterification of secondary alcs. and multi-hydroxyl compds. is one of the most valuable reactions in org. synthesis. However, it is often difficult to achieve high reaction rates and high regioselectivities with commonly used enzymes such as lipases and proteases. One of the reasons may include bulky substituents of the secondary alcs. and multi-hydroxyl compds. (e.g., carbohydrates and flavonoids). The stereospecificity pocket of lipases, which is considered as a pocket for the binding of medium substituent, might not accept a large substituent due to steric hindrance. Thereby, this review has focused on the discussion about literature survey and structural feature of the most commonly used lipase (i.e., Candida antarctica lipase B (CAL-B)) and serine-protease (i.e., subtilisin) for acylation of secondary alcs. and complex mols.
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    Schmid, R. D.; Verger, R. Lipases: Interfacial Enzymes with Attractive Applications. Angew. Chem., Int. Ed. 1998, 37, 1608– 1633,  DOI: 10.1002/(SICI)1521-3773(19980703)37:12<1608::AID-ANIE1608>3.0.CO;2-V
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    Lipases: Interfacial Enzymes with Attractive Applications
    Schmid Rolf D; Verger Robert
    Angewandte Chemie (International ed. in English) (1998), 37 (12), 1608-1633 ISSN:.
    Unusually versatile substrate specificity is shown by lipases. Not only do they hydrolyze triacylglycerols-for example, in the stomach and intestine during digestion of dietary fat-and various synthetic esters and amides, but their high stability in organic solvents permits their use in transesterification reactions and ester synthesis as well. Reactions based on lipase catalysis usually proceed with high regio- and enantioselectivity. Thus, the Ca(2+) antagonist diltiazem (1) was obtained with lipase from Serratia marcescens. Over 30 lipases have been cloned in the last few years. Since the tertiary structure of 12 lipases is known, there are presently significant efforts to improve this class of enzymes by protein engineering techniques, in view of their use in detergents and other fields of industrial application.
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    Duan, Z. Q.; Du, W.; Liu, D. H. The solvent influence on the positional selectivity of Novozym 435 during 1,3-diolein synthesis by esterication. Bioresour. Technol. 2010, 101, 2568– 2571,  DOI: 10.1016/j.biortech.2009.11.087
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    The solvent influence on the positional selectivity of Novozym 435 during 1,3-diolein synthesis by esterification
    Duan, Zhang-Qun; Du, Wei; Liu, De-Hua
    Bioresource Technology (2010), 101 (7), 2568-2571CODEN: BIRTEB; ISSN:0960-8524. (Elsevier Ltd.)
    The influence of solvents with a wide range of log P (from -0.23 to 4.5) on the positional selectivity of the immobilized lipase Novozym 435 during the esterification of oleic acid with glycerol for 1,3-diolein prepn. was investigated. Anal. was performed on the basis of a simplified kinetic model of 1,3-diolein synthesis. The results showed that the preferential selectivity of Novozym 435 to 1-position over 2-position of the glycerol mol. became weaker and weaker with the increasing log P of the solvent. But after one 1-position was acylated, the preferential selectivity to the other 1-position over 2-position would be enhanced strongly for each solvent. The study also revealed that relatively hydrophilic solvent such as t-butanol was an ideal solvent for Novozym 435 catalyzed 1,3-diolein synthesis through esterification of oleic acid with glycerol.
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    Duan, Z. Q.; Du, W.; Liu, D. H. The mechanism of solvent effect on the positional selectivity of Candida antarctica lipase B during 1,3-diolein synthesis by esterification. Bioresour. Technol. 2011, 102, 11048– 11050,  DOI: 10.1016/j.biortech.2011.09.003
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    The mechanism of solvent effect on the positional selectivity of Candida antarctica lipase B during 1,3-diolein synthesis by esterification
    Duan, Zhang-Qun; Du, Wei; Liu, De-Hua
    Bioresource Technology (2011), 102 (23), 11048-11050CODEN: BIRTEB; ISSN:0960-8524. (Elsevier Ltd.)
    We investigated the influence of solvent on the positional selectivity of Novozym 435 which was the immobilized Candida antarctica lipase B (CALB) during the esterification of oleic acid with glycerol for 1,3-diolein prepn. previously. Herein, mol. modeling was used to elucidate the underlying mechanism of the solvent effect on the positional selectivity of the enzyme. The results showed that the binding energy of sn-1 hydroxyl of glycerol mol. with CALB became higher, and the binding energy of sn-2 hydroxyl of glycerol mol. with CALB became lower along with the increase of the solvent log P. It was demonstrated that, increasing log P of the solvent, the enzyme selectivity to sn-1 hydroxyl of glycerol mol. grew weaker, and the selectivity to sn-2 hydroxyl of glycerol mol. grew stronger.
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    Uyama, H.; Klegraf, E.; Wada, S.; Kobayashi, S. Regioselective Polymerization of Sorbitol and Divinyl Sebacate Using Lipase Catalyst. Chem. Lett. 2000, 29, 800– 801,  DOI: 10.1246/cl.2000.800
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    Lang, K.; Bhattacharya, S.; Ning, Z.; Sanchez-Leija, R. J.; Bramson, M. T. K.; Centore, R.; Corr, D. T.; Linhardt, R. J.; Gross, R. A. Enzymatic polymerization of poly(glycerol-1,8-octanediol-sebacate): versatile PGS analogs that form mono-component biodegradable fiber scaffolds. Biomacromolecules 2020, 21, 3197– 3206,  DOI: 10.1021/acs.biomac.0c00641
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    Enzymatic Polymerization of Poly(glycerol-1,8-octanediol-sebacate): Versatile Poly(glycerol sebacate) Analogues that Form Monocomponent Biodegradable Fiber Scaffolds
    Lang, Kening; Bhattacharya, Somdatta; Ning, Zhuoyuan; Sanchez-Leija, Regina J.; Bramson, Michael T. K.; Centore, Robert; Corr, David T.; Linhardt, Robert J.; Gross, Richard A.
    Biomacromolecules (2020), 21 (8), 3197-3206CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    A family of poly(glycerol sebacate) (PGS) analogs were synthesized by Candida antarctica lipase B (CALB) catalysis to tailor biomaterial properties. Different fractions of glycerol (G) units in PGS were replaced by 1,8-octanediol (O) units. Poly(glycerol-1,8-octanediol-sebacate), PGOS, synthesized by CALB catalysis with a 1:3 molar ratio of G to O units has Mn and Mw values of 9500 and 92,000, resp. PGS undergoes fiber fusion during electrospinning, and cross-linked PGS rapidly resorbs when implanted. By decreasing the molar ratio of glycerol-to-octanediol from 1:1 to 1:4, the peak melting temp. (Tm) increased from 27 to 47°C. PGOS with 1:3 G to O units was electrospun into nanofibers without the need for a second component. The copolymer is semicryst. and, when cross-linked, undergoes slow in vitro mass loss (3.5 ± 1.0% in 31 days) at pH 7.4 and 37°C. Furthermore, PGOS cross-linked films have an elastic modulus of 106.1 ± 18.6 MPa, which is more than 100 times that of cross-linked PGS. New PGOS polymers showed tunable mol. wts., better thermal properties, and excellent electrospinnability. This work expanded PGS analogs' function, making these suitable biodegradable polymers for various biomedical applications.
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    d’Almeida Gameiro, M.; Goddard, A.; Taresco, V.; Howdle, S. M. Enzymatic one-pot synthesis of renewable and biodegradable surfactants in supercritical carbon dioxide (scCO2). Green Chem. 2020, 22, 1308– 1318,  DOI: 10.1039/C9GC04011K
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    Enzymatic one-pot synthesis of renewable and biodegradable surfactants in supercritical carbon dioxide (scCO2)
    d'Almeida Gameiro, Mariana; Goddard, Amy; Taresco, Vincenzo; Howdle, Steven M.
    Green Chemistry (2020), 22 (4), 1308-1318CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
    We seek to expand the opportunities to exploit glycerol, a largely untapped renewable feedstock, by exploiting enzymic catalysis in supercrit. carbon dioxide (scCO2). This work highlights a promising and clean approach to bio-renewable amphiphilic polyester-based biodegradable surfactants. We have developed a low temp. (40, 50 and 60°C), low energy melt processing route to biodegradable, renewable poly(glycerol succinate) (PGLSA) polymers that importantly have a low degree of branching (3% < DB < 11%). Our approach shows significant advantages over traditional melt polycondensation at 110-120°C, where the std. catalyst-free approach led only to highly branched (DB > 85%) or insol. crosslinked materials. We have exploited these linear PGLSA materials to create a library of 'green' surfactants by end-capping with lauric acid or poly(ethylene glycol). Our approach avoids pre-modification of the monomers and fewer synthetic steps are required. Finally, we evaluate the performance of these new surfactants, focussing upon surface tension, crit. aggregation concn. (CAC) and water contact angle.
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    Lortie, R.; Trani, M.; Ergan, F. Kinetic study of the lipase-catalyzed synthesis of triolein. Biotechnol. Bioeng. 1993, 41, 1021– 1026,  DOI: 10.1002/bit.260411104
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    Kinetic study of the lipase-catalyzed synthesis of triolein
    Lortie, Robert; Trani, Michael; Ergan, Francoise
    Biotechnology and Bioengineering (1993), 41 (11), 1021-6CODEN: BIBIAU; ISSN:0006-3592.
    The kinetics of the synthesis of triolein catalyzed by immobilized Mucor miehei lipase were studied. Equil. consts. for the synthesis of mono-, di-, and trioleins were calcd. from the equil. compns. for different initial ratios of glycerol and oleic acid by means of multiresponse regression. The 1,3-specific lipase can catalyze the synthesis of triolein because the ester (1,3-diolein) enzymically formed with the primary alc. isomerizes, through acyl migration, to form an ester (1,2-diolein) on the secondary hydroxyl. The freed primary hydroxyl may then undergo further conversion by enzyme-mediated reaction with oleate. The rates of the nonenzymic isomerization depend on the concn. of oleic acid.
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    Kapoor, M.; Gupta, M. N. Lipase promiscuity and its biochemical applications. Process Biochem. 2012, 47, 555– 569,  DOI: 10.1016/j.procbio.2012.01.011
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    Lipase promiscuity and its biochemical applications
    Kapoor, Manali; Gupta, Munishwar Nath
    Process Biochemistry (Oxford, United Kingdom) (2012), 47 (4), 555-569CODEN: PBCHE5; ISSN:1359-5113. (Elsevier Ltd.)
    A review. Lipases are the most widely used class of enzymes in org. synthesis. Availability of large no. of com. prepns., their broad specificity and relatively better stability (as compared to other enzymes) in media contg. org. solvents have all been contributing factors for this. This review has a sharp focus on their specificity. The recent results with catalytic promiscuity have shown that lipases are even more versatile than thought so far. These results have also prompted workers to rationalize the classification of specificity in terms of substrate promiscuity, condition promiscuity and catalytic promiscuity. The review also attempts to recast the known information on specificity of lipases in the context of enzyme promiscuity. Lipases can exhibit regiospecificity, specificity in terms of fatty acids, nature of the alc., and stereospecificity (distinction between sn-1 and sn-3 position on the triglyceride). Lipases show varied stability toward presence of org. solvents, extreme pH conditions and ionic liqs. In low water media, condition promiscuity in terms of esterification, transesterification and interesterification has been extensively studied. The catalytic promiscuity is being increasingly obsd. for CC bond formation reactions. Finally, the beneficial consequences of this promiscuous behavior in biotechnol. sectors are also discussed.
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    Nguyen, H. D.; Löf, D.; Hvilsted, S.; Daugaard, A. E. Highly branched bio-based unsaturated polyesters by enzymatic polymerization. Polymers 2016, 8, 363  DOI: 10.3390/polym8100363
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    Highly branched bio-based unsaturated polyesters by enzymatic polymerization
    Nguyen, Hiep Dinh; Loef, David; Hvilsted, Soeren; Daugaard, Anders Egede
    Polymers (Basel, Switzerland) (2016), 8 (10), 363/1-363/12CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
    A one-pot, enzyme-catalyzed bulk polymn. method for direct prodn. of highly branched polyesters has been developed as an alternative to currently used industrial procedures. Bio-based feed components in the form of glycerol, pentaerythritol, azelaic acid, and tall oil fatty acid (TOFA) were polymd. using an immobilized Candida antarctica lipase B (CALB) and the potential for an enzymic synthesis of alkyds was investigated. The developed method enables the use of both glycerol and also pentaerythritol (for the first time) as the alc. source and was found to be very robust. This allows simple variations in the molar mass and structure of the polyester without premature gelation, thus enabling easy tailoring of the branched polyester structure. The postpolymn. crosslinking of the polyesters illustrates their potential as binders in alkyds. The formed films had good UV stability, very high water contact angles of up to 141°and a glass transition temp. that could be controlled through the feed compn.
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    Wyatt, V. T.; Strahan, G. D. Degree of branching in hyperbranched poly(glycerol-co-diacid)s synthesized in toluene. Polymers 2012, 4, 396– 407,  DOI: 10.3390/polym4010396
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    Degree of branching in hyperbranched poly(glycerol-co-diacid)s synthesized in toluene
    Wyatt, Victor T.; Strahan, Gary D.
    Polymers (Basel, Switzerland) (2012), 4 (1), 396-407, 12 pp.CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
    1H NMR and 13C NMR spectrometry (1-dimensional and 2-dimensional) have been used to assign chem. resonances and det. the degrees of branching for polyesters synthesized by the Lewis acid (dibutyltin(IV) oxide)-catalyzed polycondensation of glycerol with either succinic acid [n (aliph. chain length) = 2], glutaric acid (n = 3), or azelaic acid (n = 7) in quasi-melt solns. with toluene. When 1:1 and 2:1 (diacid:glycerol) molar ratios were used, it was found that the glutaric acid-derived polymers gave the highest degree of polymer branching (31.2%, 85.6%, resp.) after the 24 h reaction period followed by the succinic acid-derived polymers (39.4%, 41.9%, resp.), and the azelaic acid-derived polymers (9.9%, 13.9%, resp.). Reactions performed at reflux for 24 h resulted in a 70.8% and 56.7% decrease in degree of branching for succinic acid and glutaric acid-derived polyesters, resp. There is no indication that degree of branching is significantly affected by the presence or absence of solvent according to the results obtained in this research.
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    Holter, D.; Burgath, A.; Frey, H. Degree of branching in hyperbranched polymers. Acta Polym. 1999, 50, 67– 76,  DOI: 10.1002/actp.1997.010480105
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    Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 selection guide of classical- and less classical-solvents. Green Chem. 2016, 18, 288– 296,  DOI: 10.1039/C5GC01008J
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    CHEM21 selection guide of classical- and less classical-solvents
    Prat, Denis; Wells, Andy; Hayler, John; Sneddon, Helen; McElroy, C. Robert; Abou-Shehada, Sarah; Dunn, Peter J.
    Green Chemistry (2016), 18 (1), 288-296CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
    A selection guide of common solvents has been elaborated, based on a survey of publically available solvent selection guides. In order to rank less classical solvents, a set of Safety, Health and Environment criteria is proposed, aligned with the Global Harmonized System (GHS) and European regulations. A methodol. based on a simple combination of these criteria gives an overall preliminary ranking of any solvent. This enables in particular a simplified greenness evaluation of bio-derived solvents.
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    Nijst, C. L. E.; Bruggeman, J. P.; Karp, J. M.; Ferreira, L.; Zumbuehl, A.; Bettinger, C. J.; Langer, R. Synthesis and Characterization of Photocurable Elastomers from Poly(glycerol-co-sebacate). Biomacromolecules 2007, 8, 3067– 3073,  DOI: 10.1021/bm070423u
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    Synthesis and Characterization of Photocurable Elastomers from Poly(glycerol-co-sebacate)
    Nijst, Christiaan L. E.; Bruggeman, Joost P.; Karp, Jeffrey M.; Ferreira, Lino; Zumbuehl, Andreas; Bettinger, Christopher J.; Langer, Robert
    Biomacromolecules (2007), 8 (10), 3067-3073CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Elastomeric networks are increasingly being investigated for a variety of biomedical applications including drug delivery and tissue engineering. However, in some cases, their prepn. requires the use of harsh processing conditions (e.g., high temp.), which limits their biomedical application. Herein, we demonstrate the ability to form elastomeric networks from poly(glycerol-co-sebacate) acrylate (PGSA) under mild conditions while preserving a wide range of phys. properties. These networks presented a Young's modulus between 0.05 and 1.38 MPa, an ultimate strength from 0.05 to 0.50 MPa, and elongation at break between 42% and 189% strain, by varying the degree of acrylation (DA) of PGSA. The in vitro enzymic and hydrolytic degrdn. of the polymer networks was dependent on the DA. The copolymn. of poly(ethylene glycol) diacrylate with PGSA allowed for an addnl. control of mech. properties and swelling ratios in an aq. environment, as well as enzymic and hydrolytic degrdn. Photocured PGSA networks demonstrated in vitro biocompatibility as judged by sufficient human primary cell adherence and subsequent proliferation into a confluent monolayer. These photocurable degradable elastomers could have potential application for the encapsulation of temp.-sensitive factors and cells for tissue engineering.
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    Louage, B.; Tack, L.; Wang, Y.; De Geest, B. G. Poly(glycerol sebacate) nanoparticles for encapsulation of hydrophobic anti-cancer drugs. Polym. Chem. 2017, 8, 5033– 5038,  DOI: 10.1039/C6PY02192A
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    Poly(glycerol sebacate) nanoparticles for encapsulation of hydrophobic anti-cancer drugs
    Louage, Benoit; Tack, Liesa; Wang, Yadong; De Geest, Bruno G.
    Polymer Chemistry (2017), 8 (34), 5033-5038CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    Phys. encapsulation of hydrophobic compds. into nanocarriers that are stable in aq. medium is of high interest as it can increase solubilization of the drug, lower its toxicity, control its pharmacokinetic profile and thus overall improve the therapeutic efficacy. To increase solubilization of a drug in aq. medium, the carrier should contain hydrophobic domains that can form non-covalent interactions with hydrophobic drug mols. Apart from liposomes, polymers have been widely acknowledged as promising nanocarriers. In this paper, we report the design of poly(glycerol sebacate) (PGS), an inexpensive, water insol. but biodegradable and biocompatible polymer, into nanocarriers for hydrophobic drugs. Mixing of alc. PGS solns. with water (i.e. solvent displacement) produced a fine and highly stable dispersion with a size that can be controlled by the PGS concn. and solvent to water ratio. These dispersions were used for the encapsulation of hydrophobic compds. such as a fluorescent dye and two drugs known for their anti-mitotic activity (i.e. paclitaxel (PTX) and flubendazole (FLU)). These formulations were then evaluated in vitro with cancer cells.
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    Laane, C.; Boeren, S.; Vos, K.; Veeger, C. Rules for optimization of biocatalysis in organic solvents. Biotechnol. Bioeng. 1987, 30, 81– 87,  DOI: 10.1002/bit.260300112
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    Rules for optimization of biocatalysis in organic solvents
    Laane, Colja; Boeren, Sjef; Vos, Kees; Veeger, Cees
    Biotechnology and Bioengineering (1987), 30 (1), 81-7CODEN: BIBIAU; ISSN:0006-3592.
    General rules for the optimization of different biocatalytic systems in various types of media contg. org. solvents are derived by combining data from the literature, and the logarithm of the partition coeff., log P, as a quant. measure of solvent polarity. Biocatalysis in org. solvents is low in polar solvents having a log P <2, is moderate in solvents having a log P of 2-4, and is high in apolar solvents having a log P >4. This correlation between polarity and activity parallels the ability of org. solvents to distort the essential water layer that stabilizes the biocatalysts. Further optimization of biocatalysis in org. solvents is achieved when the polarity of the microenvironment of the biocatalyst (log Pi) and the continuous org. phase (log Pcph) is tuned to the polarities of both the substrate (log Ps) and the product (log Pp) according to the following rules: |log Pi - log Ps| and |log Pcph- log Pp| should be minimal and |log Pcph - log Ps| and |log Pi - log Pp| should be maximal, with the exception that in the case of substrate inhibition log Pi should be optimized with respect to log Ps. In addn. to these simple optimization rules, the future developments of biocatalysis in org. solvents are discussed.
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    Yao, D.; Li, G.; Kuila, T.; Li, P.; Kim, N. H.; Kim, S.-I.; Lee, J. H. Lipase-Catalyzed Synthesis and Characterization of Biodegradable Polyester Containing L-Malic Acid Unit in Solvent System. J. Appl. Polym. Sci. 2011, 120, 1114– 1120,  DOI: 10.1002/app.33257
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    Lipase-catalyzed synthesis and characterization of biodegradable polyester containing L-malic acid unit in solvent system
    Yao, Da-Hu; Li, Guang-Ji; Kuila, Tapas; Li, Peng; Kim, Nam-Hoon; Kim, Seong-Il; Lee, Joong-Hee
    Journal of Applied Polymer Science (2011), 120 (2), 1114-1120CODEN: JAPNAB; ISSN:0021-8995. (John Wiley & Sons, Inc.)
    Lipase-catalyzed direct polycondensation of L-malic acid (L-MA), adipic acid, and 1,8-octanediol in org. media was achieved using Novozym 435 as the biocatalyst. 1H-NMR spectroscopy indicated that the selectivity of Novozym 435 was unaffected by changes in the org. media. The mol. wt. (Mw) of the copolymers was affected by the L-MA feed ratio in the diacids, hydrophobicity of the solvent, and soly. of the substrates in the solvents. The Mw reached a max. of 17.4 kDa at 80°C in isooctane at a L-MA feed ratio in the diacids of 40 mol %. The Mw increased from 3.2 to 16.6 kDa when the reaction time was extended from 6 to 48 h at 70°C, and remained relatively const. with further increases in reaction time from 48 to 72 h. The hydrophilicity, thermal stability, and crystallizability of the copolymer were also investigated. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011.
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    Dutta Banik, S.; Nordblad, M.; Woodley, J. M.; Peters, G. H. A Correlation between the Activity of Candida antarctica Lipase B and Differences in Binding Free Energies of Organic Solvent and Substrate. ACS Catal. 2016, 6, 6350– 6361,  DOI: 10.1021/acscatal.6b02073
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    A correlation between the activity of Candida antarctica lipase B and differences in binding free energies of organic solvent and substrate
    Dutta Banik, Sindrila; Nordblad, Mathias; Woodley, John M.; Peters, Gunther H.
    ACS Catalysis (2016), 6 (10), 6350-6361CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    The ability of enzymes to operate in org. solvent is now widely accepted and is the basis for extensive research in enzymol. The challenge is to select the solvent media that allows the modulation of enzyme activity. For a rational selection of a solvent, it is necessary to understand the effect of org. solvent mols. on enzyme structure and the enzymic reaction on a mol. level. Here, to gain such insight, the authors combined exptl. kinetic studies with full at. mol. dynamics simulations and found a correlation between the activity of Candida antarctica lipase B (CALB) [for the esterification reaction between butyric acid and EtOH at a fixed water activity] and the binding of the solvent/substrate mols. in the active site region of CALB. The authors investigated the influence of 4 org. solvents [hexane (HEX), Me tert-Bu ether (MTBE), acetonitrile (ACN), and tert-BuOH (TBU)] on the catalytic activity of CALB for the esterification reaction. The solvents were chosen on the basis of different polarity/functional groups. The study showed that these org. solvents did not alter the overall conformation of CALB; rather, the solvent effects on the performance of the enzyme may be ascribed to binding of solvent mols. to the enzyme active site region and the solvation energy of substrate mols. in the different solvents. Polar solvent mols. interacted strongly with CALB and competed with the substrate to bind to the active site region, resulting in an inhibitory effect which was also confirmed by the binding free energies for the solvent and substrate mols. estd. from the simulations. Consequently, the catalytic activity of CALB decreased in polar solvents. This effect was significant, and CALB was >10 orders of magnitude more active in nonpolar solvents (HEX and MTBE) than in the polar solvents (ACN and TBU). TBU mols. show an exceptional behavior because the solvent mol. formed an extensive H-bond network within the CALB active site region suggesting that solvent mols. rich on H-bond acceptors and donors are poor solvents when used for lipase-catalyzed esterification reactions.
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    Douka, A.; Vouyiouka, S.; Papaspyridi, L. M.; Papaspyrides, C. D. A review on enzymatic polymerization to produce polycondensation polymers: The case of aliphatic polyesters, polyamides and polyesteramides. Prog. Polym. Sci. 2018, 79, 1– 25,  DOI: 10.1016/j.progpolymsci.2017.10.001
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    A review on enzymatic polymerization to produce polycondensation polymers: The case of aliphatic polyesters, polyamides and polyesteramides
    Douka, Aliki; Vouyiouka, Stamatina; Papaspyridi, Lefki-Maria; Papaspyrides, Constantine D.
    Progress in Polymer Science (2018), 79 (), 1-25CODEN: PRPSB8; ISSN:0079-6700. (Elsevier Ltd.)
    A review on Enzymic polymn. represents today an effective and preferable alternative to conventional chem.-catalyzed processes. It offers significant advantages, summarized in the applied mild reaction conditions mainly in terms of temp. and toxicity, and high selectivity of enzymes, avoiding protection-deprotection strategies and resulting in improved quality/performance of end products. Esp. for polycondensation polymers, biocatalyzed synthetic routes have been under research for the last thirty years, including homo- and copolymn. of a significant no. of monomers. Aliph. polyesters, polyamides and at a much lower extent polyesteramides, represent the core of the pertinent studies, and are systematically discussed in the current review. Emphasis is given on polycondensates with biodegradability properties, derived from bio-based monomers such as succinic acid, 1,3- propanediol and lactide/lactic acid. Free or immobilized lipases and cutinases are the predominant biocatalysts in the relevant polymer families, being used in polycondensation as well as in ring-opening reaction schemes. The efficiency of the different biocatalytic processes is herein correlated to important process parameters, such as the enzyme and monomer type, the reaction temp. and time, the polymn. technique (soln. or solvent-free), as well as the byproduct removal method, e.g., application of vacuum, water absorption by mol. sieves, azeotropic distn.
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    Distel, K. A.; Zhu, G.; Wang, P. Biocatalysis using an organic-soluble enzyme for the preparation of poly(lactic acid) in organic solvents. Bioresour. Technol. 2005, 96, 617– 623,  DOI: 10.1016/j.biortech.2004.06.005
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    Biocatalysis using an organic-soluble enzyme for the preparation of poly(lactic acid) in organic solvents
    Distel, Kelley A.; Zhu, Guangyu; Wang, Ping
    Bioresource Technology (2005), 96 (5), 617-623CODEN: BIRTEB; ISSN:0960-8524. (Elsevier B.V.)
    Proleather from Bacillus sp. was chem. modified with decanoyl chloride for enhanced activity for the prepn. of poly(lactic acid) in org. solvents. The modified enzyme was highly sol. (up to 44 mg-protein/mL) and active in various org. solvents including chloroform, THF (THF), pyridine and acetone. The org.-sol. proleather efficiently catalyzed the polymn. of Et lactate. The reaction rate was 4-22 times that of native proleather, depending upon the solvent applied. The solubilized enzyme showed a highest activity at 50 °C, the same optimum temp. for both the native proleather and an immobilized enzyme, Novozyme-435. Denaturation of the enzymes' protein structures appeared to be the crit. factor regulating the optimum activity temp. Differential scanning calorimetry (DSC) analyses of the enzymes showed endothermic peaks around 55 °C, indicating the proteins' structures altered in that temp. range. Interestingly, the activity of the solubilized enzyme showed a more complicated water dependence as compared to native proleather.
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    Azim, H.; Dekhterman, A.; Jiang, Z.; Gross, R. A. Candida antarctica lipase B-catalyzed synthesis of poly(butylene succinate): Shorter chain building blocks also work. Biomacromolecules 2006, 7, 3093– 3097,  DOI: 10.1021/bm060574h
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    Candida antarctica Lipase B-Catalyzed Synthesis of Poly(butylene succinate): Shorter Chain Building Blocks Also Work
    Azim, Himanshu; Dekhterman, Alex; Jiang, Zhaozhong; Gross, Richard A.
    Biomacromolecules (2006), 7 (11), 3093-3097CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Lipase catalysis was successfully employed to synthesize high mol. wt. poly(butylene succinate) (PBS). Attempts to copolymerize succinic acid with 1,4-butanediol were unsuccessful due to phase sepn. of the reactants. To circumvent this problem, monophasic reaction mixts. were prepd. from di-Et succinate and 1,4-butanediol. The reactions were studied in bulk as well as in soln. Of the org. solvents evaluated, di-Ph ether was preferred, giving higher mol. wt. products. After 24 h in di-Ph ether, polymns. at 60, 70, 80, and 90 °C yielded PBS with Mn of 2000, 4000, 8000, and 7000, resp. Further increase in reaction time to 72 h resulted in little or no further increase in Mn. However, increasing the reaction time produced PBS with extraordinarily low Mw/Mn due to the diffusion and reaction between low-mol. wt. oligomers and chains that occurs at a greater frequency than interchain transesterification. Time-course studies and visual observation of polymns. at 80 °C revealed PBS ppts. at 5 to 10 h, limiting the growth of chains. To maintain a monophasic reaction mixt., the polymn. temp. was increased from 80 to 95 °C after 21 h. The result was an increase in the PBS mol. wt. to Mw = 38 000 (Mw/Mn = 1.39). This work paves the way for the synthesis of PBS macromers and polymers that contain variable quantities of monomers with chem. sensitive moieties (e.g., silicone, epoxy, vinyl). Furthermore, this study established the feasibility of using lipase catalysis to prep. polyesters from α,ω-linear aliph. di-Et ester/diol monomers with less than six carbons.
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    Mahapatro, A.; Kumar, A.; Kalra, B.; Gross, R. A. Solvent-free adipic acid/1,8-octanediol condensation polymerizations catalyzed by Candida antartica lipase B. Macromolecules 2004, 37, 35– 40,  DOI: 10.1021/ma025796w
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    Solvent-Free Adipic Acid/1,8-Octanediol Condensation Polymerizations Catalyzed by Candida antarctica Lipase B
    Mahapatro, Anil; Kumar, Ajay; Kalra, Bhanu; Gross, Richard A.
    Macromolecules (2004), 37 (1), 35-40CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Bulk condensation polymns. of adipic acid and octanediol, catalyzed by Candida antarctica Lipase B (CALB), were studied. The polymers formed by 8 and 24 h polymns. using CALB immobilized on Accurel and Lewatit had similar mol. wts. (e.g., Mn at 24 h ≈15 000). CALB "free" of the immobilization resin was also active for the polymn. but, relative to its immobilized forms, gave slower chain growth (Mn≈10,000 by 48 h). For all three catalyst systems at d.p. (DP)≥20, dispersity (Mw/Mn) was ≤1.5. Since random processes of step-growth condensation polymns. give dispersity values ≥ 2, the dispersity of products obtained using CALB as the catalyst is believed to result from the unique chain length or mass selectivity of the lipase. Gel permeation chromatograms showed that between 15 min and 4 h chain growth occurred rapidly so that the fraction of product with Mp values > 2910 increased from 28 to 78%. At 70° the catalyst activity at 4 h remained unchanged but decreased by 15 and 21% at 24 and 48 h. Unexpectedly, an increase in the concn. of CALB on Lewatit from 0.1-1% protein resulted in only a small increase in Mn (e.g., at 24 h, 14,500 vs. 17,800). However, decrease in the %protein to 0.5% had a large detrimental effect. Between 65 and 90° the polymns. occurred with little dependence on the reaction temp.
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  58. 58
    Jiang, Y.; Woortman, A. J. J.; Alberda Van Ekenstein, G. O. R.; Loos, K. Environmentally benign synthesis of saturated and unsaturated aliphatic polyesters via enzymatic polymerization of biobased monomers derived from renewable resources. Polym. Chem. 2015, 6, 5451– 5463,  DOI: 10.1039/C5PY00660K
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    Environmentally benign synthesis of saturated and unsaturated aliphatic polyesters via enzymatic polymerization of biobased monomers derived from renewable resources
    Jiang, Yi; Woortman, Albert J. J.; Alberda van Ekenstein, Gert O. R.; Loos, Katja
    Polymer Chemistry (2015), 6 (30), 5451-5463CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    Aliph. polyesters are of great interest due to their broad potential applications and sustainability. Itaconate-based aliph. polyesters are even more appealing in biomedical and pharmaceutical fields, as they are renewable functional polymers that can be biodegradable, biocompatible, and photo-curable, and might be bioresorbable. Herein, various biobased satd. aliph. polyesters and itaconate-based unsatd. aliph. polyesters are successfully produced via Candida antarctica Lipase B (CALB)-catalyzed polycondensation of (potentially) biobased di-Me itaconate, 1,4-butanediol and various diacid Et esters, using a two-stage method in di-Ph ether. The synthetic aliph. polyesters reach high ‾M‾w (wt. av. mol. wt.) values up to 94 kg mol-1. Studies on the effect of diacid Et esters on the enzymic polymn. reveal that CALB prefers diacid Et esters having a chain length of more than 2 (n > 2, n is the no. of methylene groups between the two carbonyl groups); and CALB shows the highest specificity for di-Et adipate among the tested diacid Et esters (n = 2-10). Moreover, the structure-property relationships are discussed by investigating the chem. structures, cryst. properties and thermal properties of the obtained aliph. polyesters, as well as, the thermal transitions and mech. properties of the UV cross-linked unsatd. polyesters.
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    Kuperkar, V. V.; Lade, V. G.; Prakash, A.; Rathod, V. K. Synthesis of isobutyl propionate using immobilized lipase in a solvent free system: Optimization and kinetic studies. J. Mol. Catal. B: Enzym. 2014, 99, 143– 149,  DOI: 10.1016/j.molcatb.2013.10.024
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    Synthesis of isobutyl propionate using immobilized lipase in a solvent free system: Optimization and kinetic studies
    Kuperkar, Vishakha V.; Lade, Vikesh G.; Prakash, Arushi; Rathod, Virendra K.
    Journal of Molecular Catalysis B: Enzymatic (2014), 99 (), 143-149CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
    Iso-Bu propionate is widely used in food and beverage industries as a rum flavor. This work presents the optimization and kinetic aspects of synthesis of iso-Bu propionate by esterification of propionic acid with iso-Bu alc. using immobilized lipase Novozym 435 in a solvent free system (SFS). Process parameters such as reaction time, temp., enzyme loading, speed of agitation, water concn. and acid to alc. molar ratio were optimized to achieve max. conversion. Higher conversion of 92.52% was obtained with the reaction conditions such as: temp. 40°C, enzyme loading 5% wt./wt., acid to alc. molar ratio 1:3, time 10 h and stirring speed of 300 rpm. The bisubstrate kinetic models of the enzyme catalyzed reactions namely Ordered Bi-Bi, Random Bi-Bi and Ping-Pong Bi-Bi were applied to det. the initial rates and correlated with the exptl. findings. Ping-Pong Bi-Bi model with substrate inhibition by both acid and alc. gives the best fit with parameter values as Vmax = 0.5 Mol/min/g catalyst, KA = 0.631 M, KB = 0.003 M, KiA = 0.0042 M and KiB = 0.1539 M for the concn. ranges of 2.25-10.21 M for propionic acid and 2.55-9.01 M for iso-butanol. The immobilized lipase could be reused for seven times with the conversion of acid reaching to 83%; signifies that still it can be reused for several more times. SFS is the added benefit to produce such com. valuable flavor ester.
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    Lopresto, C. G.; Calabrò, V.; Woodley, J. M.; Tufvesson, P. Kinetic study on the enzymatic esterification of octanoic acid and hexanol by immobilized Candida antarctica lipase B. J. Mol. Catal. B: Enzym. 2014, 110, 64– 71,  DOI: 10.1016/j.molcatb.2014.09.011
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    Kinetic study on the enzymatic esterification of octanoic acid and hexanol by immobilized Candida antarctica lipase B
    Lopresto, Catia Giovanna; Calabro, Vincenza; Woodley, John M.; Tufvesson, Par
    Journal of Molecular Catalysis B: Enzymatic (2014), 110 (), 64-71CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
    This study investigates reaction kinetics of the esterification of octanoic acid and hexanol into hexyl octanoate, catalyzed by an immobilized Candida antarctica lipase (Novozym 435). The product is considered natural and used as a fresh vegetable and fruity flavor additive in food, cosmetic and pharmaceutical products. The reaction is performed in n-decane as the solvent, to improve enzyme stability and to increase the reaction yield. The influence of substrate concn. on hexyl octanoate synthesis is investigated over a wide range up to 2 M. The obsd. bi-substrate inhibition pattern follows a Ping-Pong bi-bi mechanism with dead-end inhibition by both substrates and, based on the proposed model, the kinetic consts. of the esterification reaction are estd. These parameters are verified to be intrinsic - neither external nor internal mass transfer resistances are significant for the examd. reaction system - and are essential to extend anal. to a large-scale process and for a wide range of operating conditions. The progress of the reaction is also obsd. and the kinetic model is validated by fitting exptl. progress curves with two different concns. of biocatalyst. Effects of biphasicity of the reaction system, inhibition by the ester produced and the influence of the reverse reaction have been also evaluated.
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    Voit, B. I.; Lederer, A. Hyperbranched and Highly Branched Polymer Architectures-Synthetic Strategies and Major Characterization Aspects. Chem. Rev. 2009, 109, 5924– 5973,  DOI: 10.1021/cr900068q
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    Hyperbranched and Highly Branched Polymer Architectures-Synthetic Strategies and Major Characterization Aspects
    Voit, Brigitte I.; Lederer, Albena
    Chemical Reviews (Washington, DC, United States) (2009), 109 (11), 5924-5973CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. This review has covered the principle synthetic approaches toward hyperbranched polymers as well as various other highly branched polymer architectures developed over the last 20 years.
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    Zhu, X.; Zhou, Y.; Yan, D. Influence of branching architecture on polymer properties. J. Polym. Sci., Part B: Polym. Phys. 2011, 49, 1277– 1286,  DOI: 10.1002/polb.22320
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    Influence of branching architecture on polymer properties
    Zhu, Xinyuan; Zhou, Yongfeng; Yan, Deyue
    Journal of Polymer Science, Part B: Polymer Physics (2011), 49 (18), 1277-1286CODEN: JPBPEM; ISSN:0887-6266. (John Wiley & Sons, Inc.)
    A review. Hyperbranched polymers (HBPs), invented at the end of 1980s, are one important subclass of the fourth generation macromol. architectures following the linear, branched, and crosslinking polymers. Due to their unique topol. structure and interesting phys./chem. properties, HBPs have attracted wide attention from both academia and industry. HBPs are composed of linear units, dendritic units, and terminal units. The degree of branching (DB), a term to describe the compn. of these three structure units and thus the branching architecture of polymers, is one of the most important intrinsic parameters for HBPs. This review has summarized the effect of the DB on the phys. and chem. properties of HBPs, including the rheol. property, crystn. and melting behaviors, glass transition, thermal and hydrolytic degrdns., phase characteristics, lower crit. soln. temp. phase transition, optoelectronic properties, encapsulation capability, self-assembly behavior, biomedical applications, and so on. Such a structure and property relationship will build a bridge between the syntheses and applications of HBPs, esp. in the application areas of functional materials, biomedical materials, and nanotechnol. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2011.
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    Murillo, E. A.; Vallejo, P. P.; López, B. L. Characterization of hydroxylated hyperbranched polyesters of fourth and fifth generation. e-Polymers 2010, 10, 1347– 1358,  DOI: 10.1515/epoly.2010.10.1.1347
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    Xiang, F.; Stuart, M.; Vorenkamp, J.; Roest, S.; Timmer-Bosscha, H.; Stuart, M. C.; Fokkink, R.; Loontjens, T. One-pot synthesis for biocompatible amphiphilic hyperbranched polyurea micelles. Macromolecules 2013, 46, 4418– 4425,  DOI: 10.1021/ma400552x
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    One-Pot Synthesis for Biocompatible Amphiphilic Hyperbranched Polyurea Micelles
    Xiang, Fei; Stuart, Marc; Vorenkamp, Joop; Roest, Steven; Timmer-Bosscha, Hetty; Stuart, Martien Cohen; Fokkink, Remco; Loontjens, Ton
    Macromolecules (Washington, DC, United States) (2013), 46 (11), 4418-4425CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Here we report, for the first time to our knowledge, a method to synthesize AB2 monomers, the corresponding hyperbranched and the corresponding amphiphilic hyperbranched polymers in a one-pot procedure, starting from two com. available compds. Since the B groups were blocked isocyanates (BIs), the end groups of the hyperbranched polyurea were BIs as well. Coupling of a range of monomethoxy-poly(ethylene glycol)s onto the BIs yielded a platform of amphiphilic hyperbranched polymers, with controllable hydrophobic cores and hydrophilic shells. After the three consecutive reaction steps, without intermediate purifn., the final polymers were purified by pptn. in a nonsolvent, in which the polymer pptd. and the excess PEG remained dissolved. Pyrene inclusion expts. showed the formation of micelles above a crit. concn. Both cryo-EM and DLS revealed the presence of two distinct particle populations, being the primary micelles and aggregates thereof. All micelles showed a LCST behavior, with transitions close to body temp. The low cytotoxicity of the micelles make them promising for drug delivery.
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    Žagar, E.; Grdadolnik, J. An infrared spectroscopic study of H-bond network in hyperbranched polyester polyol. J. Mol. Struct. 2003, 658, 143– 152,  DOI: 10.1016/S0022-2860(03)00286-2
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    An infrared spectroscopic study of H-bond network in hyperbranched polyester polyol
    Zagar, Ema; Grdadolnik, Joze
    Journal of Molecular Structure (2003), 658 (3), 143-152CODEN: JMOSB4; ISSN:0022-2860. (Elsevier Science B.V.)
    A FTIR study of aliph. hyperbranched polyester of the fourth generation Boltorn H40 (BH40) is presented. In order to properly assign the main vibrational bands in IR spectrum temp. measurements, hydration and H/D exchange expts. were performed. Beside these expts., difference spectroscopy, 2D generalized correlation IR spectroscopy (2-DGCS) and band fitting procedure were employed to study the main interactions in polymer. On the basis of the detected interactions between various groups the structure of a H-bond network in hyperbranched polyester is proposed. Three main H-bond interactions were detected. Besides C:O···HO and HO···HO a third type of H-bond is present (C:O···HO···HO). A minor type of interactions represent the hydrogen bond formed with the carboxyl COOH group and impurities, which may be present in lower concn.
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    Godinho, B.; Gama, N.; Barros-Timmons, A.; Ferreira, A. Enzymatic synthesis of poly(glycerol sebacate) pre-polymer with crude glycerol, by-product from biodiesel prodution. AIP Conf. Proc. 2018, 1981, 020031  DOI: 10.1063/1.5045893
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    Enzymatic synthesis of poly(glycerol sebacate) pre-polymer with crude glycerol, by-product from biodiesel prodution
    Godinho, Bruno; Gama, Nuno; Barros-Timmons, Ana; Ferreira, Artur
    AIP Conference Proceedings (2018), 1981 (1, International Conference on "Times of Polymers and Composites", 2018), 020031/1-020031/4CODEN: APCPCS; ISSN:0094-243X. (American Institute of Physics)
    The biodiesel fuel technol. has attracted researchers worldwide as a viable alternative to fossil fuel consumption. The biodiesel prodn. increment has resulted in a severe waste disposal crisis, because to produce 10 Kg of biodiesel, around 1 Kg of crude glycerol is produced. Therefore, it is essential to find valuable applications for this byproduct. The biodegradable polymers have attracted interest, since many of their building blocks can be obtained from renewable sources. Poly(glycerol sebacate) (PGS) is polyester elastomer with potential biomedical applications, such, the recovery of soft tissues and organs and the delivery of pharmaceutical drugs. In this study, we report the successful synthesis of pre-polymer of PGS with Candida antarctica lipase B free (CALB) and lipase B immobilized Novozym 435 (N435) with crude glycerol and pure glycerol. The pre-polymers were analyzed by mass spectrometry MALDI-Tof-MS and RMN. (c) 2018 American Institute of Physics.
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    Brandner, J. D.; Birkmeier, R. L. Relative esterifiability of the primary and secondary hydroxyl groups of glycerol. J. Am. Oil Chem. Soc. 1960, 37, 390– 396,  DOI: 10.1007/BF02672644
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    Relative esterifiability of the primary and secondary hydroxyl groups of glycerol
    Brandner, J. D.; Birkmeier, R. L.
    Journal of the American Oil Chemists' Society (1960), 37 (), 390-6CODEN: JAOCA7; ISSN:0003-021X.
    The 2 assumptions on predicting distribution of acyl groups of Feuge and Bailey (CA 40, 62731) (a) that there is equal chance of esterification of -OH groups and (b) that there is no formation of β-monoglyceride, are re.ovrddot.examd. A test on the course of esterification of ethylene glycol with oleic acid demonstrated equal and independent activity of the primary -OH groups. This data is interpreted that it is reasonable to expect this to be true of the primary -OH groups of glycerol. Math. analyses of data from literature and by B. and B. on esterification of glycerol showed that, contrary to Feuge and Bailey, the primary and secondary -OH groups are not equally esterifiable. The equil. const. favoring esterification of primary -OH over secondary is about 2.3 at reaction temp. Since the equil. const. is substantially different at room temp. from that at reaction temp., monoglycerides as customarily prepd. are not at equil. at room temp. and undergo intramol. migration of acyl groups from β- to α-OH positions. The rate of migration depends on the phys. form of the ester and is accelerated by basic catalysts. At room temp., intermol. rearrangement occurs only over very prolonged periods. The method of calcg. relative esterifiability of primary and secondary -OH groups should be applicable to other polyols.
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    Serdarevich, B. Glyceride isomerizations in lipid chemistry. J. Am. Oil Chem. Soc. 1967, 44, 381– 393,  DOI: 10.1007/BF02666775
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    Glyceride isomerizations in lipid chemistry
    Serdarevich, B.
    Journal of the American Oil Chemists' Society (1967), 44 (7), 381-93CODEN: JAOCA7; ISSN:0003-021X.
    Acetal and ketal isomerizations in glycerides with isopropylidene and benzylidene blocking groups, and acyl migration (intramol. transesterification) in esters of carboxylic acids and H3PO4 which pose difficulties in prepn., isolation, and characterization of lipids are studied. Reaction of PhCHO with glycerol gave 4 benzylideneglycerol isomers (cis-1,2-, trans-1,2-, cis-1,3-, trans-1,3-) which were sepd. by column chromatog. and characterized by N.M.R. spectroscopy and other methods. With mono- and diglycerides having ester groups in the 2-position, the driving force in isomerization is elimination of the steric effect of branching (2-position), by conversion to stable linear forms (1-monoglycerides or 1,3-diglycerides). A slower acyl migration in diglycerides compared to monoglyceride is attributed to slower formation of the transition state ring-intermediate. In all cases ratio of isomers in isomerized products are reported. Similar data are reported for 1- and 2-glyceryl phosphates and of cyclic glyceryl phosphates by acid and base isomerization. Hydrolysis products of L-3-glycerylphosphorylcholine and 2-glycerylphosphorylcholine were sepd. by column chromatog. and characterized by periodic acid oxidn., optical rotation, and N.M.R. spectroscopy. No isomerization of unhydrolyzed L-3-glycerylphosphorylcholine and 2-glycerylphosphorylcholine was observed. Evidence indicated that acid-catalyzed hydrolyses of phosphoglycerides are under thermodynamic control whereas most basecatalyzed hydrolyses are under kinetic control. 93 references.
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    Mao, J.; Hu, Z.; Hu, J.; Zhu, X.; Xiong, H. A Density Functional Theory (DFT) study of the Acyl migration occurring during lipase-catalyzed transesterifications. Int. J. Mol. Sci. 2019, 20, 3438  DOI: 10.3390/ijms20143438
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    A density functional theory (DFT) study of the acyl migration occurring during lipase-catalyzed transesterifications
    Mao, Jinyuan; Hu, Zhenying; Hu, Jiangning; Zhu, Xuemei; Xiong, Hua
    International Journal of Molecular Sciences (2019), 20 (14), 3438pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    Acyl migration (AM) is the main side reaction in the large-scale, regio-specific lipase catalyzed prodn. of structural triglycerides (STs). A detailed understanding of the mechanism of AM was obtained during the process of lipase-catalyzed schemes (LCSs), which play a vital role in improving the quality and total yield of STs. However, currently, the mechanism of AM remains controversial. Herein, the two mechanisms (non-catalyzed (NCM) and lipase-catalyzed (LCM)) of AM have been analyzed in detail by the d. functional theory (DFT) at the mol. level. Based on the computational results, we concluded that the energy barrier of the rate-limiting step in the LCM was 18.8 kcal/mol, which is more in agreement with the available exptl. value (17.8 kcal/mol), indicating that LCM could significantly accelerate the rate of AM, because it has an energy barrier ∼2 times lower than that of the NCM. Interestingly, we also found that the catalytic triad (Asp-His-Ser) of the lipase and water could effectively drop the reaction barrier, which served as the general acid or base, or shuttle of the proton.
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    Xu, X.; Skands, A. R. H.; Høy, C. E.; Mu, H.; Balchen, S.; Adler-Nissen, J. Production of specific-structured lipids by enzymatic interesterification: Elucidation of acyl migration by response surface design. J. Am. Oil Chem. Soc. 1998, 75, 1179– 1186,  DOI: 10.1007/s11746-998-0132-6
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    Production of specific-structured lipids by enzymic interesterification: elucidation of acyl migration by response surface design
    Xu, X.; Skands, A. R. H.; Hoy, C.-E.; Mu, H.; Balchen, S.; Adler-Nissen, J.
    Journal of the American Oil Chemists' Society (1998), 75 (9), 1179-1186CODEN: JAOCA7; ISSN:0003-021X. (AOCS Press)
    Prodn. of specific-structured lipids (SSL) by lipase-catalyzed interesterification has been attracting more and more attention recently. However, it was found that acyl migration occurs during the reaction and causes the prodn. of byproducts. In this paper, the elucidation of acyl migration by response surface design was carried out in the Lipozyme IM (Rhizomucor miehei)-catalyzed interesterification between rapeseed oil and capric acid in solvent-free media. A five-factor response surface design was used to evaluate the influence of five major factors and their relationships. The five factors, water content, reaction temp., enzyme load, reaction time and substrate ratio, were varied at three levels together with two star points. All parameters besides substrate ratio had strong pos. influences on acyl migration, and reaction temp. was most significant. The contour plots clearly show the interactions between the parameters. The migration rates of different fatty acids were also compared from three different sets of expts. during the lipase-catalyzed reaction. The best-fitting quadratic response surface model was detd. by regression and backward elimination. The coeffs. of detn. (R2) of the model were 0.996 and 0.981 for Q2 value. The results show that the fitted quadratic model satisfactorily expresses acyl migration for the enzymic interesterification in the batch reactor used.
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    Laszlo, J. A.; Compton, D. L.; Vermillion, K. E. Acyl migration kinetics of vegetable oil 1,2-diacylglycerols. J. Am. Oil Chem. Soc. 2008, 85, 307– 312,  DOI: 10.1007/s11746-008-1202-5
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    Acyl migration kinetics of vegetable oil 1,2-diacylglycerols
    Laszlo, Joseph A.; Compton, David L.; Vermillion, Karl E.
    Journal of the American Oil Chemists' Society (2008), 85 (4), 307-312CODEN: JAOCA7; ISSN:0003-021X. (Springer)
    The acyl migration kinetics of long-chain 1,2-diacylglycerol (1,2-DAG) to form 1,3-diacylglycerol (1,3-DAG) over the temp. range of 25-80 °C were examd. using 1H-NMR spectroscopy. Lipase-catalyzed propanolysis of high-oleic sunflower oil, followed by a series of solvent extn. steps, generated high purity 1,2-DAG (0.93 mol fraction of the DAG content). The 1,2-DAG mole fraction of 0.32 at equil. was found to be insensitive to temp., indicating that long-chain acyl group migration is neither endothermic nor exothermic. Detn. of the temp.-dependent, first-order reaction kinetic parameters revealed a 1,2-DAG half life (t1/2) of 3,425 h and 15.8 h at 25 and 80 °C, resp. A comparison of 1,2-DAG with 2-monoacylglycerol indicated that there is no difference between the two in the potential energy state (ΔG‡) of their resp. transitions states or cyclic intermediates.
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    Compton, D. L.; Vermillion, K. E.; Laszlo, J. A. Acyl migration kinetics of 2-Monoacylglycerols from soybean oil via 1H NMR. J. Am. Oil Chem. Soc. 2007, 84, 343– 348,  DOI: 10.1007/s11746-007-1049-1
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    Acyl migration kinetics of 2-monoacylglycerols from soybean oil via 1H NMR
    Compton, David L.; Vermillion, Karl E.; Laszlo, Joseph A.
    Journal of the American Oil Chemists' Society (2007), 84 (4), 343-348CODEN: JAOCA7; ISSN:0003-021X. (Springer)
    The acyl migration kinetics of neat 2-monoacylglycerol (2-MAG) to form 1-MAG was detd. using 1H NMR spectroscopy to monitor the β-proton integration ratios of the two species over time. 2-MAG was synthesized by the Novozym 435-catalyzed alcoholysis of soybean oil and isolated by solvent extn. or mol. distn. at a mole fraction (X2-MAG) of 0.94 relative to total MAG. The kinetics parameters of the neat 2-MAG acyl migration were investigated over the temp. range of 23-80°. The 2-MAG mol. fraction remained unchanged at 23° over the course of 168 h and reached an equil. of X2-MAG = 0.09 at only 80°. Modeling of the kinetics data revealed a 2-MAG half life (t1/2) of 3,500 and 22.8 h at 23 and 80°, resp., with an activation energy of 79.0±6.5 kJ mol-1. The use of 1H NMR spectroscopy proved an expedient method for monitoring the acyl migration in 2-MAG compared to other reported methods (e.g. GC, HPLC, and 13C-NMR spectroscopy), requiring no sample manipulation and minimizing the deleterious effects of high temps. and solvent exposure.
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  • Abstract

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    Figure 1

    Figure 1. (a) Substitution pattern of PGS composed of the terminal (1T and 2T), linear (1,3L and 1,2L), and dendritic (1,2,3D) glyceridic units as indicated by the (b) 1H NMR spectrum in (CD3)2CO.

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    Figure 2

    Figure 2. Degree of branching (DB) and the average number of dendritic units per PGS chain (n1,2,3D), determined by 1H NMR, and the number average molecular weight (Mn) as a function of reaction time as determined by 1H NMR and GPC analyses for reactions performed in acetone at (a) 30 °C and (b) 40 °C.

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    Figure 3

    Figure 3. GPC chromatograms illustrating the temporal evolution of the molecular weight and molecular weight distribution of the PGS prepared in (a) tetrahydrofuran, (b) tert-butanol, (c) acetone, and (d) acetonitrile at 40 °C. The dashed lines indicate the retention volume related to the PS standard with the lowest molecular weight (1050 g mol–1) at 33 mL.

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    Figure 4

    Figure 4. Number average degree of polymerization (Dpn) as a function of reaction time for reactions performed in (a) tetrahydrofuran, (b) tert-butanol, (c) acetone, and (d) acetonitrile. (e) Apparent rate constant (kapp) as a function of temperature.

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    Figure 5

    Figure 5. Number average degree of polymerization (Dpn, box solid) and the average molar fraction (xi) of glycerol (gray circle open) and glyceridic units 1T (maroon circle open), 2T (purple circle open), 1,3L (blue circle open), 1,2L (green circle open), and 1,2,3D (red circle open) in the reaction medium as a function of reaction time for reactions performed in acetone at (a) 30 °C, (b) 40 °C, and (c) 50 °C.

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    Figure 6

    Figure 6. Molar ratio of glyceridic units as a function of time for reactions performed in acetone at 30 °C (□), 40 °C (○), and 50 °C (Δ): (a) x1T/x2T and (b) x1,3L/x1,2L.

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    Scheme 1

    Scheme 1. Representation of the Mechanism of Glycerol-Based Polyester Chain Growth and Branching during the Simultaneous Occurrence of the CALB-Catalyzed Esterification and Acyl Migration (A.M.)
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  • References

    This article references 77 other publications.

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      Rai, R.; Tallawi, M.; Grigore, A.; Boccaccini, A. R. Synthesis, properties and biomedical applications of poly(glycerol sebacate) (PGS): A review. Prog. Polym. Sci. 2012, 37, 1051– 1078,  DOI: 10.1016/j.progpolymsci.2012.02.001
      1
      Synthesis, properties and biomedical applications of poly(glycerol sebacate) (PGS): A review
      Rai, Ranjana; Tallawi, Marwa; Grigore, Alexandra; Boccaccini, Aldo R.
      Progress in Polymer Science (2012), 37 (8), 1051-1078CODEN: PRPSB8; ISSN:0079-6700. (Elsevier Ltd.)
      A review. Poly(glycerol sebacate) (PGS) is a biodegradable polymer increasingly used in a variety of biomedical applications. This polyester is prepd. by polycondensation of glycerol and sebacic acid. PGS exhibits biocompatibility and biodegradability, both highly relevant properties in biomedical applications. PGS also involves cost effective prodn. with the possibility of up scaling to industrial prodn. In addn., the mech. properties and degrdn. kinetics of PGS can be tailored to match the requirements of intended applications by controlling curing time, curing temp., reactants concn. and the degree of acrylation in acrylated PGS. Because of the flexible and elastomeric nature of PGS, its biomedical applications have mainly targeted soft tissue replacement and the engineering of soft tissues, such as cardiac muscle, blood, nerve, cartilage and retina. However, applications of PGS are being expanded to include drug delivery, tissue adhesive and hard tissue (i.e., bone) regeneration. The design and fabrication of PGS based devices for applications that mimic native physiol. conditions are also being pursued. Novel designs range from accordion-like honeycomb structures for cardiac patches, gecko-like surfaces for tissue adhesives to PGS (nano) fibers for extra cellular matrix (ECM) like constructs; new design avenues are being investigated to meet the ever growing demand for replacement tissues and organs. In less than a decade PGS has become a material of great scrutiny and interest by the biomedical research community. In this review the authors consolidate the valuable existing knowledge in the fields of synthesis, properties and biomedical applications of PGS and PGS-related biomaterials and devices.
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      Zamboulis, A.; Nakiou, E. A.; Christodoulou, E.; Bikiaris, D. N. Polyglycerol Hyperbranched Polyesters: Synthesis, Properties and Pharmaceutical and Biomedical Applications. Int. J. Mol. Sci. 2019, 20, 6210  DOI: 10.3390/ijms20246210
      2
      Polyglycerol hyperbranched polyesters: synthesis, properties and pharmaceutical and biomedical applications
      Zamboulis, Alexandra; Nakiou, Eirini A.; Christodoulou, Evi; Bikiaris, Dimitrios N.; Kontonasaki, Eleana; Liverani, Liliana; Boccaccini, Aldo R.
      International Journal of Molecular Sciences (2019), 20 (24), 6210CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      A review. In a century when environmental pollution is a major issue, polymers issued from bio-based monomers have gained important interest, as they are expected to be environment-friendly, and biocompatible, with non-toxic degrdn. products. In parallel, hyperbranched polymers have emerged as an easily accessible alternative to dendrimers with numerous potential applications. Glycerol (Gly) is a natural, low-cost, trifunctional monomer, with a prodn. expected to grow significantly, and thus an excellent candidate for the synthesis of hyperbranched polyesters for pharmaceutical and biomedical applications. In the present article, we review the synthesis, properties, and applications of glycerol polyesters of aliph. dicarboxylic acids (from succinic to sebacic acids) as well as the copolymers of glycerol or hyperbranched polyglycerol with poly(lactic acid) and poly(ε-caprolactone). Emphasis was given to summarize the synthetic procedures (monomer molar ratio, used catalysts, temps., etc.,) and their effect on the mol. wt., soly., and thermal and mech. properties of the prepd. hyperbranched polymers. Their applications in pharmaceutical technol. as drug carries and in biomedical applications focusing on regenerative medicine are highlighted.
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    3. 3
      Loh, X. J.; Karim, A. A.; Owh, C. Poly(glycerol sebacate) biomaterial: synthesis and biomedical applications. J. Mater. Chem. B 2015, 3, 7641– 7652,  DOI: 10.1039/C5TB01048A
      3
      Poly(glycerol sebacate) biomaterial: synthesis and biomedical applications
      Loh, Xian Jun; Abdul Karim, Anis; Owh, Cally
      Journal of Materials Chemistry B: Materials for Biology and Medicine (2015), 3 (39), 7641-7652CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
      A review. The recently developed poly(glycerol sebacate) (PGS) has been gaining attraction as a biomaterial for tissue engineering applications. Reported in 2002, a simple polycondensation method was developed to synthesize PGS for soft tissue engineering applications. It has since become a highly sought after biomaterial due to its soft, robust and flexible characteristics and it is relatively low cost compared to other biodegradable elastomers currently available in the market. We summarize in this review, the various synthetic approaches of PGS and highlight selected applications in nerve guidance, soft tissue regeneration, vascular and myocardial tissue regeneration, blood vessel reconstruction, drug delivery, and the replacement of photoreceptor cells. A crit. assessment of the material is provided as a scope for future improvement. The future outlook of this material is also provided at the end of this review.
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      Wang, Y.; Ameer, G. A.; Sheppard, B. J.; Langer, R. A tough biodegradable elastomer. Nat. Biotechnol. 2002, 20, 602– 606,  DOI: 10.1038/nbt0602-602
      4
      A tough biodegradable elastomer
      Wang, Yadong; Ameer, Guillermo A.; Sheppard, Barbara J.; Langer, Robert
      Nature Biotechnology (2002), 20 (6), 602-606CODEN: NABIF9; ISSN:1087-0156. (Nature America Inc.)
      Biodegradable polymers have significant potential in biotechnol. and bioengineering. However, for some applications, they are limited by their inferior mech. properties and unsatisfactory compatibility with cells and tissues. A strong, biodegradable, and biocompatible elastomer could be useful for fields such as tissue engineering, drug delivery, and in vivo sensing. We designed, synthesized, and characterized a tough biodegradable elastomer from biocompatible monomers. This elastomer forms a covalently crosslinked, three-dimensional network of random coils with hydroxyl groups attached to its backbone. Both crosslinking and the hydrogen-bonding interactions between the hydroxyl groups likely contribute to the unique properties of the elastomer. In vitro and in vivo studies show that the polymer has good biocompatibility. Polymer implants under animal skin are absorbed completely within 60 days with restoration of the implantation sites to their normal architecture.
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    5. 5
      Li, Y.; Cook, W. D.; Moorhoff, C.; Huang, W.; Chen, Q. Synthesis, characterization and properties of biocompatible poly(glycerol sebacate) pre-polymer and gel. Polym. Int. 2013, 62, 534– 547,  DOI: 10.1002/pi.4419
      5
      Synthesis, characterization and properties of biocompatible poly(glycerol sebacate) pre-polymer and gel
      Li, Yuan; Cook, Wayne D.; Moorhoff, Cornelis; Huang, Wen-Chao; Chen, Qi-Zhi
      Polymer International (2013), 62 (4), 534-547CODEN: PLYIEI; ISSN:0959-8103. (John Wiley & Sons Ltd.)
      Poly(glycerol sebacate) (PGS) is an elastomer with potential biomedical applications but it suffers from problems with irreproducible synthesis and the unacceptable toxicity of very soft PGS elastomers. To establish the reason for these problems, PGS was synthesized using different temps. and reaction times, and the reaction was monitored by titrn. of the unreacted carboxylic groups and measurement of the mass loss during synthesis. It was found that evapn. of glycerol was a major cause of irreproducibility of the elastomer synthesis and this was more significant at higher reaction temps. The polymer microstructure was analyzed using NMR spectroscopy and all twelve acylglyceride 13C-signals as well as two small extra peaks of the residual glycerol were obsd. for the pre-polymer. For the PGS gel, the glyceride moieties were characterized using NMR spectroscopy for the first time. The modulus and ultimate tensile strength of the gel increased with longer cure times and at higher cure temps. while the elongation to break decreased and this was interpreted in terms of network theory. The cell viability of mouse fibroblasts was better for PGS samples with a higher conversion.© 2012 Society of Chem. Industry.
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    6. 6
      Chen, Q.; Bismarck, A.; Hansen, U.; Junaid, S.; Tran, M. Q.; Harding, S. E.; Ali, N. N.; Boccaccini, A. R. Characterisation of a soft elastomer poly(glycerol sebacate) designed to match the mechanical properties of myocardial tissue. Biomaterials 2008, 29, 47– 57,  DOI: 10.1016/j.biomaterials.2007.09.010
      6
      Characterisation of a soft elastomer poly(glycerol sebacate) designed to match the mechanical properties of myocardial tissue
      Chen Qi-Zhi; Bismarck Alexander; Hansen Ulrich; Junaid Sarah; Tran Michael Q; Harding Sian E; Ali Nadire N; Boccaccini Aldo R
      Biomaterials (2008), 29 (1), 47-57 ISSN:0142-9612.
      The myocardial tissue lacks significant intrinsic regenerative capability to replace the lost cells. Therefore, the heart is a major target of research within the field of tissue engineering, which aims to replace infarcted myocardium and enhance cardiac function. The primary objective of this work was to develop a biocompatible, degradable and superelastic heart patch from poly(glycerol sebacate) (PGS). PGS was synthesised at 110, 120 and 130 degrees C by polycondensation of glycerol and sebacic acid with a mole ratio of 1:1. The investigation was focused on the mechanical and biodegrading behaviours of the developed PGS. PGS materials synthesised at 110, 120 and 130 degrees C have Young's moduli of 0.056, 0.22 and 1.2 MPa, respectively, which satisfy the mechanical requirements on the materials applied for the heart patch and 3D myocardial tissue engineering construction. Degradation assessment in phosphate buffered saline and Knockout DMEM culture medium has demonstrated that the PGS has a wide range of degradability, from being degradable in a couple of weeks to being nearly inert. The matching of physical characteristics to those of the heart, the ability to fine tune degradation rates in biologically relevant media and initial data showing biocompatibility indicate that this material has promise for cardiac tissue engineering applications.
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    7. 7
      Li, X.; Hong, A. T.; Naskar, N.; Chung, H. Criteria for Quick and Consistent Synthesis of Poly (glycerol sebacate) for Tailored Mechanical Properties. Biomacromolecules 2015, 16, 1525– 1533,  DOI: 10.1021/acs.biomac.5b00018
      7
      Criteria for Quick and Consistent Synthesis of Poly(glycerol sebacate) for Tailored Mechanical Properties
      Li, Xinda; Hong, Albert T.-L.; Naskar, Nilanjon; Chung, Hyun-Joong
      Biomacromolecules (2015), 16 (5), 1525-1533CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Poly(glycerol sebacate) (PGS) and its derivs. make up an attractive class of biomaterial owing to their tunable mech. properties with programmable biodegradability. In practice, however, the application of PGS is often hampered by frequent inconsistency in reproducing process conditions. The inconsistency stems from the volatile nature of glycerol during the esterification process. In this study, we suggest that the degree of esterification (DE) can be used to predict precisely the phys. status, the mech. properties, and the degrdn. of the PGS materials. Young's modulus is shown to linearly increase with DE, which is in agreement with an entropic spring theory of rubbers. To provide a processing guideline for researchers, we also provide a phys. status map as a function of curing temp. and time. The amt. of glycerol loss, obtainable by monitoring the evolution of the total mass loss and the DE during synthesis, is shown to make the predictions even more precise. We expect that these strategies can be applicable to different categories of polymers that involve condensation polymn. with the volatility of the reactants. In addn., we demonstrate that microwave-assisted prepolymn. is a time- and energy-efficient pathway to obtain PGS. For example, 15 min of microwave time is shown to be as efficient as prepolymn. in nitrogen atm. for 6 h at 130 °C. The quick synthesis method, however, causes a severe evapn. of glycerol, resulting in a large distortion in the monomer ratio between glycerol and sebacic acid. Consequently, more rigid PGS is produced under a similar curing condition compared to the conventional prepolymn. method. Finally, we demonstrate that the addn. of molecularly rigid crosslinking agents and network-structured inorg. nanoparticles are also effective in enhancing the mech. properties of the PGS-derived materials.
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    8. 8
      Barrett, D. G.; Yousaf, M. N. Design and applications of biodegradable polyester tissue scaffolds based on endogenous monomers found in human metabolism. Molecules 2009, 14, 4022– 4050,  DOI: 10.3390/molecules14104022
      8
      Design and applications of biodegradable polyester tissue scaffolds based on endogenous monomers found in human metabolism
      Barrett, Devin G.; Yousaf, Muhammad N.
      Molecules (2009), 14 (10), 4022-4050CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)
      A review. Synthetic polyesters have deeply impacted various biomedical and engineering fields, such as tissue scaffolding and therapeutic delivery. Currently, many applications involving polyesters are being explored with polymers derived from monomers that are endogenous to the human metab. Examples of these monomers include glycerol, xylitol, sorbitol, and lactic, sebacic, citric, succinic, α-ketoglutaric, and fumaric acids. In terms of mech. versatility, crystallinity, hydrophobicity, and biocompatibility, polyesters synthesized partially or completely from these monomers can display a wide range of properties. The flexibility in these macromol. properties allows for materials to be tailored according to the needs of a particular application. Along with the presence of natural monomers that allows for a high probability of biocompatibility, there is also an added benefit that this class of polyesters is more environmentally friendly than many other materials used in biomedical engineering. While the selection of monomers may be limited by nature, these polymers have produced or have the potential to produce an enormous no. of successes in vitro and in vivo.
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    9. 9
      Wang, Y.; Kim, Y. M.; Langer, R. In vivo degradation characteristics of poly(glycerol sebacate). J. Biomed. Mater. Res., Part A 2003, 66A, 192– 197,  DOI: 10.1002/jbm.a.10534
      9
      In vivo degradation characteristics of poly(glycerol sebacate)
      Wang, Yadong; Kim, Yu Mi; Langer, Robert
      Journal of Biomedical Materials Research, Part A (2003), 66A (1), 192-197CODEN: JBMRCH ISSN:. (John Wiley & Sons, Inc.)
      The authors have developed a series of biodegradable elastomers, poly(glycerol sebacate) (PGS), based on glycerol and sebacic acid. The polymers are potentially useful in soft tissue regeneration and engineering. To evaluate the performance of PGS in a physiol. environment, the authors compared their degrdn. profiles with poly(DL-lactide-co-glycolide) (50:50, carboxyl ended, Mw 15,000) in vivo. Among the parameters examd. are changes in wt. and mech. strength with time, implant geometry, surface characteristics, and degree of swelling. Unlike poly(DL-lactide-co-glycolide), PGS primarily degrades by surface erosion, which gives a linear degrdn. profile of mass, preservation of geometry and intact surface, and retention of mech. strength.
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    10. 10
      Cai, W.; Liu, L. Shape-memory effect of poly(glycerol – sebacate) elastomer. Mater. Lett. 2008, 62, 2171– 2173,  DOI: 10.1016/j.matlet.2007.11.042
      There is no corresponding record for this reference.
    11. 11
      Mortensen, P. B. C6-C10-dicarboxylic aciduria in starved, fat-fed and diabetic rats receiving decanoic acid or medium-chain triacylglycerol. An in vivo measure of the rate of beta-oxidation of fatty acids. Biochim. Biophys. Acta, Lipids Lipid Metab. 1981, 664, 349– 355,  DOI: 10.1016/0005-2760(81)90057-6
      11
      C6-C10-dicarboxylic aciduria in starved, fat-fed and diabetic rats receiving decanoic acid or medium-chain triacylglycerol. An in vivo measure of the rate of β-oxidation of fatty acids
      Mortensen, Per Broebech
      Biochimica et Biophysica Acta, Lipids and Lipid Metabolism (1981), 664 (2), 349-55CODEN: BBLLA6; ISSN:0005-2760.
      Administration of decanoic acid to rats resulted not only in elevated urinary excretions of the C10-dicarboxylic acid (sebacic acid), but also in highly elevated excretions of the β-oxidn. products C8- and C6-dicarboxylic acids (suberic and adipic acids). Activation of the lipid metab. by starvation, fat-feeding, and exptl. diabetes increased the excretions of adipic acid and decreased the excretions of sebacic acid, i.e. the rate of oxidn. of fatty acids was correlated with the adipic:sebacic acid ratio in urine. Compared with nondiabetic unstarved rats, the adipic:sebacic acid ratio was elevated 2-3-, 8-16-, 5-19-, and 22-88-fold in rats which were, resp., starved for 2 days, starved for 4 days, on a fat-free diet for 4 days, and ketotic due to streptozotocin-induced diabetes. All rats with ratios >10 were ketotic (urinary excretions of 3-hydroxybutyric acid >500 μg/mg creatinine) and all rats with ratios <4 were nonketotic; ketosis was a variable finding in rats with intermediary ratios. Similar changes in the ratio of excreted dicarboxylic acids were found when medium-chain triacylglycerols were fed instead of decanoic acid.
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    12. 12
      Liu, G.; Hinch, B.; Beavis, A. D. Mechanisms for the Transport of α,ω-Dicarboxylates through the Mitochondrial Inner Membrane. J. Biol. Chem. 1996, 271, 25338– 25344,  DOI: 10.1074/jbc.271.41.25338
      12
      Mechanisms for the transport of α,ω-dicarboxylates through the mitochondrial inner membrane
      Liu, Guoying; Hinch, Bryan; Beavis, Andrew D.
      Journal of Biological Chemistry (1996), 271 (41), 25338-25344CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      α,ω-Dicarboxylates have antibacterial properties, have been used in the treatment of hyperpigmentary disorders, are active against various melanoma cell lines, and can also undergo β-oxidn. Little, however, is known about their transport. In this paper, we examine the mitochondrial transport of α,ω-dicarboxylates ranging from oxalate (DC2) to sebacate (DC10). DC2-DC10 are transported by the inner membrane anion channel (IMAC). DC6-DC10 are also transported by an electroneutral mechanism that appears to reflect transport of the acid through the lipid bilayer. AT 37°C and pH 7.0, DC10 is transported very rapidly at 3 μmol/min·mg, and respiring mitochondria swell in the K+ salts of these acids. This transport mechanism is probably the major pathway by which the longer dicarboxylates enter cells, bacteria, and mitochondria. We also demonstrate that DC5-DC10 can also be transported by an electroneutral mechanism mediated by tributyltin, a potent inhibitor of IMAC. The mechanism appears to involve electroneutral exchange of a TBT-dicarboxylate-H complex for TBT-OH. Finally, we present evidence that of all the dicarboxylates tested only DC2-DC4 can be transported by the classical dicarboxylate carrier.
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    13. 13
      Sundback, C. A.; Shyu, J. Y.; Wang, Y.; Faquin, W.; Langer, R. S.; Vacanti, J. P.; Hadlock, T. A. Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material. Biomaterials 2005, 26, 5454– 5464,  DOI: 10.1016/j.biomaterials.2005.02.004
      13
      Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material
      Sundback, Cathryn A.; Shyu, Jeffery Y.; Wang, Yadong; Faquin, William C.; Langer, Robert S.; Vacanti, Joseph P.; Hadlock, Tessa A.
      Biomaterials (2005), 26 (27), 5454-5464CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      No satisfactory method currently exists for bridging neural defects. Autografts lead to inadequate functional recovery, and most available artificial neural conduits possess unfavorable swelling and pro-inflammatory characteristics. This study examd. the biocompatibility of a novel biodegradable elastomer, poly(glycerol sebacate) (PGS), for neural reconstruction applications, as the material possesses favorable mech. property and degrdn. characteristics. The effect of PGS on Schwann cell metabolic activity, attachment, proliferation, and apoptosis were examd. in vitro in comparison with poly(lactide-co-glycolide) (PLGA), a biomaterial widely utilized for tissue engineering applications. The in vivo tissue response to PGS was compared with PLGA implanted juxtaposed to the sciatic nerve; the phys. changes in the implant material were measured during the degrdn. process. PGS had no deleterious effect on Schwann cell metabolic activity, attachment, or proliferation, and did not induce apoptosis; the in vitro effects of PGS were similar to or superior to that of PLGA. In vivo, PGS demonstrated a favorable tissue response profile compared with PLGA, with significantly less inflammation and fibrosis and without detectable swelling during degrdn. PGS is an excellent candidate material for neural reconstruction applications given its lack of in vitro Schwann cell toxicity and minimal in vivo tissue response.
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    14. 14
      Lau, C. C.; Bayazit, M. K.; Knowles, J. C.; Tang, J. Tailoring degree of esterification and branching of poly(glycerol sebacate) by energy efficient microwave irradiation. Polym. Chem. 2017, 8, 3937– 3947,  DOI: 10.1039/C7PY00862G
      14
      Tailoring degree of esterification and branching of poly(glycerol sebacate) by energy efficient microwave irradiation
      Lau, Chi Ching; Bayazit, Mustafa Kemal; Knowles, Jonathan Campbell; Tang, Junwang
      Polymer Chemistry (2017), 8 (26), 3937-3947CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Poly(glycerol sebacate) (PGS) is known as an exciting biomaterial owing to its tunable mech. properties and controllable degrdn. rate. However, it is always challenging to control these properties. In this study, we have proposed a solvent-based system to provide a better control of reaction temp. in a microwave cavity, which can minimize evapn. of monomers, and water was collected to analyze the degree of esterification. Pre-PGSs with varied degrees of esterification were prepd. using both single mode and multimode microwave cavity irradn. (MI) in this solvent-based reaction system. For a similar degree of esterification of pre-PGSs, the reaction time was almost halved with a better control on mech. properties by single mode MI compared to multimode MI. Furthermore, the single mode MI approach was compared with the conventional heating (CH) approach. The mech. properties and degrdn. rate of PGSs can be controlled readily by using the single mode MI approach compared to CH, which are crucial for their application as a biomaterial. It has been found that the single mode MI not only accelerates the pre-polymn. process rate by six times, but also speeds up the curing time to the same extent. The Young's modulus of PGSs prepd. by single mode MI is increased from 0.77 to 3.14 MPa when the degree of esterification is 66.82%, which is 50% higher than that reported in the literature. Furthermore, PGS using a highly branched pre-PGS prepd. by the single mode MI method has a large degree of flexibility. It can achieve a much higher Young's modulus than that obtained by CH with a short curing time (<10 h). In addn., the residual mass of PGSs prepd. by single mode MI is varied from 78.54% to 92.96% compared to the CH method that ranges from 84.24% to 93.31%. Thus, these highly branched PGSs produced by single mode MI also show a wider degrdn. window (approx. 59% higher degree of flexibility than the CH method), which is found to be highly dependent on the degree of esterification and curing time of the pre-polymer, and controlled by branching.
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    15. 15
      Conejero-garcía, Á.; Gimeno, H. R.; Sáez, Y. M.; Vilariño-feltrer, G.; Ortuño-lizarán, I.; Vallés-lluch, A. Correlating synthesis parameters with physicochemical properties of poly(glycerol sebacate). Eur. Polym. J. 2017, 87, 406– 419,  DOI: 10.1016/j.eurpolymj.2017.01.001
      15
      Correlating synthesis parameters with physicochemical properties of poly(glycerol sebacate)
      Conejero-Garcia, Alvaro; Gimeno, Hector Rivero; Saez, Yolanda Moreno; Vilarino-Feltrer, Guillermo; Ortuno-Lizaran, Isabel; Valles-Lluch, Ana
      European Polymer Journal (2017), 87 (), 406-419CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)
      Poly(glycerol sebacate), PGS, is an elastomeric biodegradable polyester increasingly proposed in a variety of biomedical applications. It is prepd. by polycondensation of sebacic acid and glycerol in a first stage in which a prepolymer is obtained, followed by a curing to conveniently crosslink it. In this work, synthesis parameters such as the curing temp. and time, and the molar ratio between reactants, were systematically varied to correlate them with the physicochem. properties of the resulting polymer networks. The efficiency of each manufg. process was quantified through the relative mass effectively crosslinked and insol. in THF. IR spectra gave an estn. of the ratio of non-condensed polar terminal groups. These results were correlated with swelling results, which in turn provided the means to calc. the chains d. through Flory-Rehner equil. swelling equation for lightly crosslinked polymers. The role of the synthesis parameters on the phys. state of the resulting polymers, as well as their proneness to hydrolyze, were followed. The results obtained highlight the relevance of rinsing them following synthesis, to remove non-crosslinked chains that easily diffuse to the surrounding medium. Curing under mild conditions equimolar mixts. of sebacic acid and glycerol proved to lead to poorly crosslinked swellable networks, which hydrolyze easily in bulk mode. Alternative molar ratios yield sticky and difficult to handle materials at higher polyol fractions in the reactive mixt., while an excess of acid terminal groups leads to a faster mass loss by hydrolysis in aq. media together with surface salts deposition, concomitant with a lesser cell viability in in vitro culture. PGS synthesized from an equimolar ratio between reactants and cured at 130 °C or higher, for 48 h or longer, show suitable features for their use in tissue engineering applications where hydrophobic surface-degradable rubbers are required, without significant differences among them.
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    16. 16
      Maliger, R.; Halley, P. J.; Cooper-White, J. J. Poly(glycerol-sebacate) bioelastomers-kinetics of step-growth reactions using Fourier Transform (FT)-Raman spectroscopy. J. Appl. Polym. Sci. 2013, 127, 3980– 3986,  DOI: 10.1002/app.37719
      16
      Poly(glycerol-sebacate) bioelastomers-kinetics of step-growth reactions using Fourier Transform (FT)-Raman spectroscopy
      Maliger, Raju; Halley, Peter J.; Cooper-White, Justin J.
      Journal of Applied Polymer Science (2013), 127 (5), 3980-3986CODEN: JAPNAB; ISSN:0021-8995. (John Wiley & Sons, Inc.)
      Kinetic studies of the esterification of glycerol (G) and sebacic acid (SA) at three molar ratios (0.6, 0.8, 1.0) and at three temps. (120, 130, 140°C) to form poly(glycerol-sebacate) were performed and assessed using FT-Raman spectroscopy. The quant. changes in the concns. of carboxylic acid and ester groups within the forming bioelastomer were measured and the chem. rate consts. (k) detd. from the kinetic scheme were first-order, with respect to sebacic acid concn. Increasing the reaction temp. by 20°C is noted to increase the chem. rate const. (k) by a factor of up to 4.5 and the total extent of conversion at early times for the molar ratios investigated. The activation energy (Ea) and the pre-exponential factor (A0) for these three stoichiometric ratios were calcd., which varied in accordance with the av. functionality of the system. Under isothermal conditions, the chem. rate const. remained unchanged with an increase in the extent of the reaction (α) until a spontaneous transition resulted in the shift in the mechanism from kinetics to diffusion controlled. The Young's moduli of the PGS polymers were found to depend primarily on the av. functionality of the system and the curing period. This investigation confirms the reaction mechanism for PGS polymer synthesis and shows the flexibility afforded to PGS properties and reaction times through varying the stoichiometric ratios of glycerol to sebacic acid. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2012.
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    17. 17
      You, Z.; Cao, H.; Gao, J.; Shin, P. H.; Day, B. W.; Wang, Y. A functionalizable polyester with free hydroxyl groups and tunable physiochemical and biological properties. Biomaterials 2010, 31, 3129– 3138,  DOI: 10.1016/j.biomaterials.2010.01.023
      17
      A functionalizable polyester with free hydroxyl groups and tunable physiochemical and biological properties
      You, Zhengwei; Cao, Haiping; Gao, Jin; Shin, Paul H.; Day, Billy W.; Wang, Yadong
      Biomaterials (2010), 31 (12), 3129-3138CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Polyesters with free functional groups allow facile modifications with biomols., which can lead to versatile biomaterials that afford controlled interactions with cells and tissues. Efficient synthesis of functionalizable polyesters (Functionalizable polymer is defined as a polymer with functional groups that readily react with biomols. and functionalized biomaterial as one already modified with biomols.) is still a challenge that greatly limits the availability and widespread applications of biofunctionalized synthetic polymers. Here we report a simple route to prep. a functionalizable polyester, poly(sebacoyl diglyceride) (PSeD) bearing free hydroxyl groups. The key synthetic step is an epoxide ring-opening polymn., instead of the traditional polycondensation that produces poly(glycerol sebacate) (PGS). PSeD has a more defined structure with mostly linear backbone, more free hydroxyl groups, higher mol. wt., and lower polydispersity than PGS. Crosslinking PSeD with sebacic acid yields a polymer five times tougher and more elastic than cured PGS. PSeD exhibits good cytocompatibility in vitro. Furthermore, functionalization by glycine proceeds with high efficiency. This versatile synthetic platform can offer a large family of biodegradable, functionalized polymers with tunable physiochem. and biol. properties useful for a wide range of biomedical applications.
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    18. 18
      You, Z.; Bi, X.; Wang, Y. Fine Control of Polyester Properties via Epoxide ROP Using Monomers Carrying Diverse Functional Groups. Macromol. Biosci. 2012, 12, 822– 829,  DOI: 10.1002/mabi.201200035
      18
      Fine Control of Polyester Properties via Epoxide ROP Using Monomers Carrying Diverse Functional Groups
      You, Zhengwei; Bi, Xiaoping; Wang, Yadong
      Macromolecular Bioscience (2012), 12 (6), 822-829CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Synthetic biodegradable polymers are important biomaterials. However, most of them are biol. inert. Free functional groups can allow easy biofunctionalization. Efficient introduction of functional groups to biodegradable polymers is still a challenge. Here, a practical strategy is presented to synthesize various functional polyesters with free hydroxyl groups polymd. via epoxide ring-opening polymn. (ROP) between dicarboxylic acids and diglycidyl dicarboxylates without protection and deprotection. The polymers exhibit a wide range of phys., thermal, and mech. properties, and good cytocompatibilities. This synthetic platform is expected to lead to functional polymers useful for a wide variety of biomedical applications.
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    19. 19
      Slavko, E.; Taylor, M. S. Catalyst-controlled polycondensation of glycerol with diacyl chlorides: Linear polyesters from a trifunctional monomer. Chem. Sci. 2017, 8, 7106– 7111,  DOI: 10.1039/C7SC01886J
      19
      Catalyst-controlled polycondensation of glycerol with diacyl chlorides: linear polyesters from a trifunctional monomer
      Slavko, Ekaterina; Taylor, Mark S.
      Chemical Science (2017), 8 (10), 7106-7111CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      Diarylborinic acids catalyze the formation of linear polyesters from glycerol, a trifunctional, carbohydrate-based monomer. The selective activation of 1,2-diols over isolated alcs. by the organoboron catalyst results in polymers that are essentially free of branching or crosslinking and possess a high fraction of 1,3-enchained glycerol units, as assessed by 1H and 13C NMR spectroscopy. The ability to generate well-defined polyester architectures from glycerol is significant in light of the numerous applications of such macromols., particularly in the biomedical area. Isomerization, post-polymn. functionalization and controlled crosslinking reactions of the obtained linear poly(glycerol esters) are demonstrated.
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    20. 20
      Kline, B. J.; Beckman, E. J.; Russell, A. J. One-step biocatalytic synthesis of linear polyesters with pendant hydroxyl groups. J. Am. Chem. Soc. 1998, 120, 9475– 9480,  DOI: 10.1021/ja9808907
      20
      One-Step Biocatalytic Synthesis of Linear Polyesters with Pendant Hydroxyl Groups
      Kline, Billie J.; Beckman, Eric J.; Russell, Alan J.
      Journal of the American Chemical Society (1998), 120 (37), 9475-9480CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The chem. synthesis of linear polyesters with various hydrophilic functional groups is difficult, involving a multistep reaction pathway and synthesis of a suitable monomer with a protected functional group. A straightforward conventional synthesis from a trifunctional compd., such as glycerol, and a diester or dicarboxylic acid to produce a polyester results in the formation of networks. An alternative approach to the one-step synthesis of aliph. hydroxyl-substituted polyesters from divinyl adipate (DVA) and various triols has been found by utilizing the intrinsic specificity of an enzyme. The wt. av. mol. wts. of the resulting polyesters vary according to the triol used and range from ∼3,000 to 14,000 Da. Anal. by MALDI-TOF mass spectrometry has confirmed the presence of a linear polyester with hydroxyl substituents, and there is no evidence for network formation. The pendant groups are 90-95% secondary and 5-10% primary hydroxyl groups. Exptl. detn. of hydroxyl no. verifies that one hydroxyl group is present on each repeat unit of the substituted polyester. By the addn. of increasing amts. of 1,4-butanediol to the reaction mixt. of glycerol and DVA, predictable and sensitive control of the hydroxyl no. can be accomplished.
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    21. 21
      Iglesias, L. E.; Fukuyama, Y.; Nonami, H.; Erra-Balsells, R.; Baldessari, A. A simple enzymatic procedure for the synthesis of a hydroxylated polyester from glycerol and adipic acid. Biotechnol. Tech. 1999, 13, 923– 926,  DOI: 10.1023/A:1008958212814
      21
      A simple enzymatic procedure for the synthesis of a hydroxylated polyester from glycerol and adipic acid
      Iglesias, Luis E.; Fukuyama, Yuko; Nonami, Hiroshi; Erra-Balsells, Rosa; Baldessari, Alicia
      Biotechnology Techniques (1999), 13 (12), 923-926CODEN: BTECE6; ISSN:0951-208X. (Kluwer Academic Publishers)
      Lipase B from Candida antarctica regioselectively catalyzed the polyesterification of glycerol with adipic acid. UV-MALDI-TOF-MS anal. of the polymers shows low mol. wt. polyesters (1314-1716) with very narrow polydispersities (1.0-1.2).
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    22. 22
      Rao, Z. K.; Ni, H. L.; Li, Y.; Zhu, H. Y.; Liu, Y.; Hao, J. Y. Macroscopic Scaffold Control for Lipase-Catalyzed Dendritic Polyol-Polyesters. Macromol. Chem. Phys. 2019, 220, 1900048  DOI: 10.1002/macp.201900048
      There is no corresponding record for this reference.
    23. 23
      Zeng, F.; Yang, X.; Li, D.; Dai, L.; Zhang, X.; Lv, Y.; Wei, Z. Functionalized polyesters derived from glycerol: Selective polycondensation methods toward glycerol-based polyesters by different catalysts. J. Appl. Polym. Sci. 2019, 48574  DOI: 10.1002/app.48574
      There is no corresponding record for this reference.
    24. 24
      Uyama, H.; Inada, K.; Kobayashi, S. Regioselective polymerization of divinyl sebacate and triols using lipase catalyst. Macromol. Rapid. Commun. 1999, 20, 171– 174,  DOI: 10.1002/(SICI)1521-3927(19990401)20:4<171::AID-MARC171>3.0.CO;2-2
      24
      Regioselective polymerization of divinyl sebacate and triols using lipase catalyst
      Uyama, Hiroshi; Inada, Kojiro; Kobayashi, Shiro
      Macromolecular Rapid Communications (1999), 20 (4), 171-174CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH)
      The lipase-catalyzed regioselective polymn. of divinyl sebacate and triols was carried out. Immobilized lipase derived from Candida antarctica induces the polymn. of divinyl sebacate and glycerol, yielding a sol. polymer of relatively high mol. wt. NMR anal. showed that 1,3-diglyceride is a main unit and the branching unit (triglyceride) is contained in the resulting polymer. These data indicate that the polymn. proceeds regioselectively to give the reactive polyester having a pendant OH group.
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    25. 25
      Uyama, H.; Inada, K.; Kobayashi, S. Regioselectivity Control in Lipase-Catalyzed Polymerization of Divinyl Sebacate and Triols. Macromol. Biosci. 2001, 1, 40– 44,  DOI: 10.1002/1616-5195(200101)1:1<40::AID-MABI40>3.0.CO;2-T
      25
      Regioselectivity control in lipase-catalyzed polymerization of divinyl sebacate and triols
      Uyama, Hiroshi; Inada, Kojiro; Kobayashi, Shiro
      Macromolecular Bioscience (2001), 1 (1), 40-44CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH)
      The polymn. of divinyl sebacate and 3 different triols (glycerol, 1,2,4-butanetriol, and 1,2,6-hexanetriol) in presence of lipase catalyst was studied by variation of reaction parameters (i.e., temp. and feed ratio of monomers) as well as enzyme origin (i.e., lipases derived from Candida antarctica, Muco miehei, and Pseudomonas cepacia). The resulting polymers were examd. by size exclusion chromatog. and various 13C NMR techniques (microstructure). By proper selection of conditions, regiospecific polymn. at the α,ω-position of the triol was achieved, yielding a linear polymer having a reactive OH-group in the main chain.
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    26. 26
      Kumar, A.; Kulshrestha, A. S.; Gao, W.; Gross, R. A. Versatile Route to Polyol Polyesters by Lipase Catalysis. Macromolecules 2003, 36, 8219– 8221,  DOI: 10.1021/ma0351827
      26
      Versatile Route to Polyol Polyesters by Lipase Catalysis
      Kumar, Ajay; Kulshrestha, Ankur S.; Gao, Wei; Gross, Richard A.
      Macromolecules (2003), 36 (22), 8219-8221CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      A simple and versatile strategy to perform regioselective lipase-catalyzed condensation polymns. between diacids and reduced sugar polyols is described. Sorbitol and glycerol were reacted with adipic acid under Novozyme-435 catalysis in absence and presence of 1,8-octanediol to produce related polyol terpolyesters rich in OH functionality. Soly., thermal stability, melting transitions, and crystallinity of the polyol terpolyesters were studied.
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    27. 27
      Kulshrestha, A. S.; Gao, W.; Gross, R. A. Glycerol copolyesters: Control of branching and molecular weight using a lipase catalyst. Macromolecules 2005, 38, 3193– 3204,  DOI: 10.1021/ma0480190
      27
      Glycerol Copolyesters: Control of Branching and Molecular Weight Using a Lipase Catalyst
      Kulshrestha, Ankur S.; Gao, Wei; Gross, Richard A.
      Macromolecules (2005), 38 (8), 3193-3204CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Immobilized Lipase B from Candida antartica (Novozyme 435) catalyzed bulk polycondensations at 70 °C for 42 h that resulted in hyperbranched polyesters with octanediol-adipate and glycerol-adipate repeat units. Instead of using org. solvents, the monomers adipic acid (A2), 1,8-octanediol (B2), and glycerol (B'B2) were combined to form monophasic ternary mixts. During the first 18 h of a copolymn. with monomer feed ratio (A2 to B2 to B'B2) 1.0:0.8:0.2 mol/mol, the regioselectivity of Novozyme 435 resulted in linear copolyesters. Extending the reaction to 42 h gave hyperbranched copolymers with dendritic glycerol units. The % regioselectivity for esterifications at the primary glycerol positions ranged from 77 to 82% and was independent of glycerol content in the monomer feed. Variation of glycerol in the monomer feed gave copolymers with degree of branching (DB) from 9 to 58%. In one example, a hyperbranched copolyester with 18 mol % glycerol-adipate units was formed in 90% yield, with Mw 75 600 (by SEC-MALLS), Mw/Mn 3.1, and DB 19%. Generalized structures were created to depict that for hyperbranched glycerol copolyesters and the progression of products formed at reaction times from 5 min to 42 h.
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    28. 28
      Kallinteri, P.; Higgins, S.; Hutcheon, G. A.; St. Pourçain, C. B.; Garnett, M. C. Novel functionalized biodegradable polymers for nanoparticle drug delivery systems. Biomacromolecules 2005, 6, 1885– 1894,  DOI: 10.1021/bm049200j
      28
      Novel Functionalized Biodegradable Polymers for Nanoparticle Drug Delivery Systems
      Kallinteri, Paraskevi; Higgins, Sean; Hutcheon, Gillian A.; St. Pourcain, Christopher B.; Garnett, Martin C.
      Biomacromolecules (2005), 6 (4), 1885-1894CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      We have prepd. and screened a library of novel functionalized polymers for development of nanoparticle drug delivery systems. The polymer backbone consisting of two ester-linked, non-toxic, biol. monomers, glycerol and adipic acid, was prepd. using a hydrolytic enzyme. The specificity of the chosen enzyme yields a linear polymer with one free pendant hydroxyl group per repeat unit, which can be further functionalized. This protocol gives control over the backbone polymer mol. wt., together with the ability to incorporate various amts. of different fatty acyl substituents. These functionalized polymers are able to self-assemble into well-defined small particles of high homogeneity with a very low toxicity. They are able to incorporate a water sol. drug, dexamethasone phosphate, with a high efficiency and drug loading which varies with the polymer specification. The above characteristics strongly suggest that these polymers could be developed into useful nanoparticulate drug delivery systems.
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    29. 29
      Yang, Y.; Lu, W.; Cai, J.; Hou, Y.; Ouyang, S.; Xie, W.; Gross, R. A. Poly(oleic diacid-co-glycerol): Comparison of polymer structure resulting from chemical and lipase catalysis. Macromolecules 2011, 44, 1977– 1985,  DOI: 10.1021/ma102939k
      29
      Poly(oleic diacid-co-glycerol): comparison of polymer structure resulting from chemical and lipase catalysis
      Yang, Yixin; Lu, Wenhua; Cai, Jiali; Hou, Yu; Ouyang, Suyang; Xie, Wenchun; Gross, Richard A.
      Macromolecules (Washington, DC, United States) (2011), 44 (7), 1977-1985CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      This study compares the synthesis and structure of poly(oleic diacid-co-glycerol) that results by using immobilized Candida antarctica Lipase B (Novozym 435, N435) and di-Bu tin oxide (DBTO) as catalysts. By using N435 catalysis and an oleic diacid to glycerol molar ratio of 1.0:1.0, the resulting polyester no.-av. mol. wts. (Mn) were 6000 g/mol at 6 h and 9100 g/mol at 24 h with low branching degree (Den% of glycerol 13%-16%). 13C NMR spectra of these polyesters revealed their chain-ends consist exclusively of monosubstituted glycerol units. Further diversification in polymer structure was achieved by using N435 catalysis and by changing the feed ratio of oleic diacid to glycerol from 1.0:1.0 to 1.5:1.0 in 0.1 increments. Resulting polyesters were not crosslinked (no obsd. gel fraction), had similar Mn values (generally between 4800 and 6000 g/mol), but differed in dendritic unit content, glycerol unit degree of substitution, and end-group structure (monosubstituted glyercol vs. carboxyl end-groups). In contrast, by using DBTO as catalyst and an oleic diacid to glycerol molar ratio of 1.0:1.0, polyester Mn of 1700 g/mol was obtained at 6 h and, thereafter, a gel was formed due to crosslinking. As a consequence of N435's ability to deter crosslink reactions owing to steric hindrance at the active site, a family of unique, sol., hyperbranched copolyesters was formed.
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    30. 30
      Naolou, T.; Weiss, V. M.; Conrad, D.; Busse, K.; Mäder, K.; Kressler, J. Fatty Acid Modified Poly(glycerol adipate) - Polymeric Analogues of Glycerides. In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C.; Kressler, J., Eds.; ACS Symposium Series; American Chemical Society: Washington, 2013; Chapter 4, pp 39– 52.
      There is no corresponding record for this reference.
    31. 31
      Taresco, V.; Creasey, R. G.; Kennon, J.; Mantovani, G.; Alexander, C.; Burley, J. C.; Garnett, M. C. Variation in structure and properties of poly(glycerol adipate) via control of chain branching during enzymatic synthesis. Polymer 2016, 89, 41– 49,  DOI: 10.1016/j.polymer.2016.02.036
      31
      Variation in structure and properties of poly(glycerol adipate) via control of chain branching during enzymatic synthesis
      Taresco, V.; Creasey, R. G.; Kennon, J.; Mantovani, G.; Alexander, C.; Burley, J. C.; Garnett, M. C.
      Polymer (2016), 89 (), 41-49CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)
      Poly (glycerol adipate) (PGA) can be produced from divinyl adipate and unprotected glycerol by an enzymic route to generate a polymer with relatively low molar mass (12 kDa). PGA bears a pendant hydroxyl group which imparts a hydrophilic character to this water insol. polymer. We have examd. the effect of synthesis temp. on polymer characteristics through various techniques including FT-IR, 1H and 13C NMR, surface and thermal anal., both to expand the data already present in the literature about this material and to understand better its properties for potential pharmaceutical applications. The use of a lipase (Novozym 435) as a catalyst suppresses crosslinking at the pendant glyceryl hydroxyl through steric hindrance at the active site, thus producing polymers with low degrees of branching (5-30%), and removes the need for any pre- or post-polymn. protection/deprotection reactions. Careful temp. control during synthesis can give polymers with reproducible mol. wts. and reduced amts. of polymer branching compared to synthesis at higher temps. Due to the ability of the synthetic route to produce a range of structures, PGA generated by enzymic routes may emerge as a useful biodegradable polymer platform to engineer solid dispersions or nanoparticles for healthcare applications.
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    32. 32
      Valerio, O.; Misra, M.; Mohanty, A. K. Poly(glycerol-co-diacids) Polyesters: From Glycerol Biorefinery to Sustainable Engineering Applications, A Review. ACS Sustainable Chem. Eng. 2018, 6, 5681– 5693,  DOI: 10.1021/acssuschemeng.7b04837
      32
      Poly(glycerol-co-diacids) Polyesters: From Glycerol Biorefinery to Sustainable Engineering Applications, A Review
      Valerio, Oscar; Misra, Manjusri; Mohanty, Amar K.
      ACS Sustainable Chemistry & Engineering (2018), 6 (5), 5681-5693CODEN: ASCECG; ISSN:2168-0485. (American Chemical Society)
      A review. Upgrading of biobased glycerol to com. products is a necessary step on sustainable development of oleaginous biomass biorefining. The synthesis of poly(glycerol-co-diacid) polyester materials is an attractive option for glycerol usage that can produce a wide range of products of com. interest. These polymeric materials could be used on industrial applications as biomedical devices, surfactants and in thermoplastic material development. In this review, the process engineering aspects leading to tailorable polymeric products are comprehensively analyzed with emphasis on control of mol. architecture and functionality. Mol. wt., degree of branching, mech. properties and surface chem. of the materials can be controlled by fine tuning synthesis procedures to match custom specifications in end products. Potential usage of poly(glycerol-co-diacid) materials with tailored physicochem. properties on industrially relevant applications is presented. Advantages and challenges in the synthesis of these novel polymeric materials for value added application are addressed and discussed.
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    33. 33
      Ortiz, C.; Ferreira, M. L.; Barbosa, O.; dos Santos, J. C. S.; Rodrigues, R. C.; Berenguer-Murcia, Á.; Briand, L. E.; Fernandez-Lafuente, R. Novozym 435: The ‘perfect’ lipase immobilized biocatalyst?. Catal. Sci. Technol. 2019, 9, 2380– 2420,  DOI: 10.1039/C9CY00415G
      33
      Novozym 435: the "perfect" lipase immobilized biocatalyst?
      Ortiz, Claudia; Ferreira, Maria Lujan; Barbosa, Oveimar; dos Santos, Jose C. S.; Rodrigues, Rafael C.; Berenguer-Murcia, Angel; Briand, Laura E.; Fernandez-Lafuente, Roberto
      Catalysis Science & Technology (2019), 9 (10), 2380-2420CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
      A review. Novozym 435 (N435) is a com. available immobilized lipase produced by Novozymes. It is based on immobilization via interfacial activation of lipase B from Candida antarctica on a resin, Lewatit VP OC 1600. This resin is a macroporous support formed by poly(Me methacrylate) crosslinked with divinylbenzene. N435 is perhaps the most widely used com. biocatalyst in both academy and industry. Here, we review some of the success stories of N435 (in chem., energy and lipid manipulation), but we focus on some of the problems that the use of this biocatalyst may generate. Some of these problems are just based on the mechanism of immobilization (interfacial activation) that may facilitate enzyme desorption under certain conditions. Other problems are specific to the support: mech. fragility, moderate hydrophilicity that permits the accumulation of hydrophilic compds. (e.g., water or glycerin) and the most crit. one, support dissoln. in some org. media. Finally, some solns. (N435 coating with silicone, enzyme phys. or chem. crosslinking, and use of alternative supports) are proposed. However, the N435 history, even with these problems, may continue in the coming future due to its very good properties if some simpler alternative biocatalysts are not developed.
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    34. 34
      Yoon, K. R.; Hong, S. P.; Kong, B.; Choi, I. S. Polycondensation of sebacic acid with primary and secondary hydroxyl groups containing diols catalyzed by Candida antarctica lipase B. Synth. Commun. 2012, 42, 3504– 3512,  DOI: 10.1080/00397911.2011.585267
      34
      Polycondensation of Sebacic Acid with Primary and Secondary Hydroxyl Groups Containing Diols Catalyzed by Candida antarctica Lipase B
      Yoon, Kuk Ro; Hong, Suk-Pyo; Kong, Bokyung; Choi, Insung S.
      Synthetic Communications (2012), 42 (23), 3504-3512CODEN: SYNCAV; ISSN:0039-7911. (Taylor & Francis, Inc.)
      The aliph. polyesters are normally synthesized by ester interchange reactions or direct esterification of hydroxyacids or diacid/diol combinations. Biotransformation, utilizing the enzymes as catalysts, was accepted as an alternative route for the synthesis of aliph. polyesters and offers various advantages compared with the conventional, metal-catalyzed polymn. reactions. Previous studies indicated that lipase-catalyzed polycondensation reactions between diols and diacids occurred preferentially at primary hydroxyl groups of diols, when diols contained both primary and secondary hydroxyl groups. In this work, we investigated lipase-catalyzed polycondensation of diacids and secondary hydroxyl group-contg. diols, and successfully synthesized polyesters by polycondensation with secondary hydroxyl groups as well as primary hydroxyl groups. Various diols, glycerol, 1,2-propanediol, 1,3-butanediol, 2,3-butanediol, and 2,4-pentanediol were tested for the polycondensation. The polymn. was achieved by heating a mixt. of lipase B, sebacic acid, and the diols in anhyd. toluene at 100 °C for 72 h. The resulting polymers were characterized by 1H and 13C NMR spectroscopy, Fourier transform-IR spectroscopy, thermogravimetric anal., and gel permeation chromatog.
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    35. 35
      Cha, H. J.; Park, J. B.; Park, S. Esterification of Secondary Alcohols and Multi-hydroxyl Compounds by Candida antarctica Lipase B and Subtilisin. Biotechnol. Bioprocess. Eng. 2019, 24, 41– 47,  DOI: 10.1007/s12257-018-0379-1
      35
      Esterification of Secondary Alcohols and Multi-hydroxyl Compounds by Candida antarctica Lipase B and Subtilisin
      Cha, Hee-Jeong; Park, Jin-Byung; Park, Seongsoon
      Biotechnology and Bioprocess Engineering (2019), 24 (1), 41-47CODEN: BBEIAU; ISSN:1226-8372. (Korean Society for Biotechnology and Bioengineering)
      Enzyme-catalyzed esterification of secondary alcs. and multi-hydroxyl compds. is one of the most valuable reactions in org. synthesis. However, it is often difficult to achieve high reaction rates and high regioselectivities with commonly used enzymes such as lipases and proteases. One of the reasons may include bulky substituents of the secondary alcs. and multi-hydroxyl compds. (e.g., carbohydrates and flavonoids). The stereospecificity pocket of lipases, which is considered as a pocket for the binding of medium substituent, might not accept a large substituent due to steric hindrance. Thereby, this review has focused on the discussion about literature survey and structural feature of the most commonly used lipase (i.e., Candida antarctica lipase B (CAL-B)) and serine-protease (i.e., subtilisin) for acylation of secondary alcs. and complex mols.
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    36. 36
      Schmid, R. D.; Verger, R. Lipases: Interfacial Enzymes with Attractive Applications. Angew. Chem., Int. Ed. 1998, 37, 1608– 1633,  DOI: 10.1002/(SICI)1521-3773(19980703)37:12<1608::AID-ANIE1608>3.0.CO;2-V
      36
      Lipases: Interfacial Enzymes with Attractive Applications
      Schmid Rolf D; Verger Robert
      Angewandte Chemie (International ed. in English) (1998), 37 (12), 1608-1633 ISSN:.
      Unusually versatile substrate specificity is shown by lipases. Not only do they hydrolyze triacylglycerols-for example, in the stomach and intestine during digestion of dietary fat-and various synthetic esters and amides, but their high stability in organic solvents permits their use in transesterification reactions and ester synthesis as well. Reactions based on lipase catalysis usually proceed with high regio- and enantioselectivity. Thus, the Ca(2+) antagonist diltiazem (1) was obtained with lipase from Serratia marcescens. Over 30 lipases have been cloned in the last few years. Since the tertiary structure of 12 lipases is known, there are presently significant efforts to improve this class of enzymes by protein engineering techniques, in view of their use in detergents and other fields of industrial application.
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    37. 37
      Duan, Z. Q.; Du, W.; Liu, D. H. The solvent influence on the positional selectivity of Novozym 435 during 1,3-diolein synthesis by esterication. Bioresour. Technol. 2010, 101, 2568– 2571,  DOI: 10.1016/j.biortech.2009.11.087
      37
      The solvent influence on the positional selectivity of Novozym 435 during 1,3-diolein synthesis by esterification
      Duan, Zhang-Qun; Du, Wei; Liu, De-Hua
      Bioresource Technology (2010), 101 (7), 2568-2571CODEN: BIRTEB; ISSN:0960-8524. (Elsevier Ltd.)
      The influence of solvents with a wide range of log P (from -0.23 to 4.5) on the positional selectivity of the immobilized lipase Novozym 435 during the esterification of oleic acid with glycerol for 1,3-diolein prepn. was investigated. Anal. was performed on the basis of a simplified kinetic model of 1,3-diolein synthesis. The results showed that the preferential selectivity of Novozym 435 to 1-position over 2-position of the glycerol mol. became weaker and weaker with the increasing log P of the solvent. But after one 1-position was acylated, the preferential selectivity to the other 1-position over 2-position would be enhanced strongly for each solvent. The study also revealed that relatively hydrophilic solvent such as t-butanol was an ideal solvent for Novozym 435 catalyzed 1,3-diolein synthesis through esterification of oleic acid with glycerol.
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    38. 38
      Duan, Z. Q.; Du, W.; Liu, D. H. The mechanism of solvent effect on the positional selectivity of Candida antarctica lipase B during 1,3-diolein synthesis by esterification. Bioresour. Technol. 2011, 102, 11048– 11050,  DOI: 10.1016/j.biortech.2011.09.003
      38
      The mechanism of solvent effect on the positional selectivity of Candida antarctica lipase B during 1,3-diolein synthesis by esterification
      Duan, Zhang-Qun; Du, Wei; Liu, De-Hua
      Bioresource Technology (2011), 102 (23), 11048-11050CODEN: BIRTEB; ISSN:0960-8524. (Elsevier Ltd.)
      We investigated the influence of solvent on the positional selectivity of Novozym 435 which was the immobilized Candida antarctica lipase B (CALB) during the esterification of oleic acid with glycerol for 1,3-diolein prepn. previously. Herein, mol. modeling was used to elucidate the underlying mechanism of the solvent effect on the positional selectivity of the enzyme. The results showed that the binding energy of sn-1 hydroxyl of glycerol mol. with CALB became higher, and the binding energy of sn-2 hydroxyl of glycerol mol. with CALB became lower along with the increase of the solvent log P. It was demonstrated that, increasing log P of the solvent, the enzyme selectivity to sn-1 hydroxyl of glycerol mol. grew weaker, and the selectivity to sn-2 hydroxyl of glycerol mol. grew stronger.
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    39. 39
      Uyama, H.; Klegraf, E.; Wada, S.; Kobayashi, S. Regioselective Polymerization of Sorbitol and Divinyl Sebacate Using Lipase Catalyst. Chem. Lett. 2000, 29, 800– 801,  DOI: 10.1246/cl.2000.800
      There is no corresponding record for this reference.
    40. 40
      Lang, K.; Bhattacharya, S.; Ning, Z.; Sanchez-Leija, R. J.; Bramson, M. T. K.; Centore, R.; Corr, D. T.; Linhardt, R. J.; Gross, R. A. Enzymatic polymerization of poly(glycerol-1,8-octanediol-sebacate): versatile PGS analogs that form mono-component biodegradable fiber scaffolds. Biomacromolecules 2020, 21, 3197– 3206,  DOI: 10.1021/acs.biomac.0c00641
      40
      Enzymatic Polymerization of Poly(glycerol-1,8-octanediol-sebacate): Versatile Poly(glycerol sebacate) Analogues that Form Monocomponent Biodegradable Fiber Scaffolds
      Lang, Kening; Bhattacharya, Somdatta; Ning, Zhuoyuan; Sanchez-Leija, Regina J.; Bramson, Michael T. K.; Centore, Robert; Corr, David T.; Linhardt, Robert J.; Gross, Richard A.
      Biomacromolecules (2020), 21 (8), 3197-3206CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      A family of poly(glycerol sebacate) (PGS) analogs were synthesized by Candida antarctica lipase B (CALB) catalysis to tailor biomaterial properties. Different fractions of glycerol (G) units in PGS were replaced by 1,8-octanediol (O) units. Poly(glycerol-1,8-octanediol-sebacate), PGOS, synthesized by CALB catalysis with a 1:3 molar ratio of G to O units has Mn and Mw values of 9500 and 92,000, resp. PGS undergoes fiber fusion during electrospinning, and cross-linked PGS rapidly resorbs when implanted. By decreasing the molar ratio of glycerol-to-octanediol from 1:1 to 1:4, the peak melting temp. (Tm) increased from 27 to 47°C. PGOS with 1:3 G to O units was electrospun into nanofibers without the need for a second component. The copolymer is semicryst. and, when cross-linked, undergoes slow in vitro mass loss (3.5 ± 1.0% in 31 days) at pH 7.4 and 37°C. Furthermore, PGOS cross-linked films have an elastic modulus of 106.1 ± 18.6 MPa, which is more than 100 times that of cross-linked PGS. New PGOS polymers showed tunable mol. wts., better thermal properties, and excellent electrospinnability. This work expanded PGS analogs' function, making these suitable biodegradable polymers for various biomedical applications.
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    41. 41
      d’Almeida Gameiro, M.; Goddard, A.; Taresco, V.; Howdle, S. M. Enzymatic one-pot synthesis of renewable and biodegradable surfactants in supercritical carbon dioxide (scCO2). Green Chem. 2020, 22, 1308– 1318,  DOI: 10.1039/C9GC04011K
      41
      Enzymatic one-pot synthesis of renewable and biodegradable surfactants in supercritical carbon dioxide (scCO2)
      d'Almeida Gameiro, Mariana; Goddard, Amy; Taresco, Vincenzo; Howdle, Steven M.
      Green Chemistry (2020), 22 (4), 1308-1318CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      We seek to expand the opportunities to exploit glycerol, a largely untapped renewable feedstock, by exploiting enzymic catalysis in supercrit. carbon dioxide (scCO2). This work highlights a promising and clean approach to bio-renewable amphiphilic polyester-based biodegradable surfactants. We have developed a low temp. (40, 50 and 60°C), low energy melt processing route to biodegradable, renewable poly(glycerol succinate) (PGLSA) polymers that importantly have a low degree of branching (3% < DB < 11%). Our approach shows significant advantages over traditional melt polycondensation at 110-120°C, where the std. catalyst-free approach led only to highly branched (DB > 85%) or insol. crosslinked materials. We have exploited these linear PGLSA materials to create a library of 'green' surfactants by end-capping with lauric acid or poly(ethylene glycol). Our approach avoids pre-modification of the monomers and fewer synthetic steps are required. Finally, we evaluate the performance of these new surfactants, focussing upon surface tension, crit. aggregation concn. (CAC) and water contact angle.
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    42. 42
      Lortie, R.; Trani, M.; Ergan, F. Kinetic study of the lipase-catalyzed synthesis of triolein. Biotechnol. Bioeng. 1993, 41, 1021– 1026,  DOI: 10.1002/bit.260411104
      42
      Kinetic study of the lipase-catalyzed synthesis of triolein
      Lortie, Robert; Trani, Michael; Ergan, Francoise
      Biotechnology and Bioengineering (1993), 41 (11), 1021-6CODEN: BIBIAU; ISSN:0006-3592.
      The kinetics of the synthesis of triolein catalyzed by immobilized Mucor miehei lipase were studied. Equil. consts. for the synthesis of mono-, di-, and trioleins were calcd. from the equil. compns. for different initial ratios of glycerol and oleic acid by means of multiresponse regression. The 1,3-specific lipase can catalyze the synthesis of triolein because the ester (1,3-diolein) enzymically formed with the primary alc. isomerizes, through acyl migration, to form an ester (1,2-diolein) on the secondary hydroxyl. The freed primary hydroxyl may then undergo further conversion by enzyme-mediated reaction with oleate. The rates of the nonenzymic isomerization depend on the concn. of oleic acid.
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    43. 43
      Kapoor, M.; Gupta, M. N. Lipase promiscuity and its biochemical applications. Process Biochem. 2012, 47, 555– 569,  DOI: 10.1016/j.procbio.2012.01.011
      43
      Lipase promiscuity and its biochemical applications
      Kapoor, Manali; Gupta, Munishwar Nath
      Process Biochemistry (Oxford, United Kingdom) (2012), 47 (4), 555-569CODEN: PBCHE5; ISSN:1359-5113. (Elsevier Ltd.)
      A review. Lipases are the most widely used class of enzymes in org. synthesis. Availability of large no. of com. prepns., their broad specificity and relatively better stability (as compared to other enzymes) in media contg. org. solvents have all been contributing factors for this. This review has a sharp focus on their specificity. The recent results with catalytic promiscuity have shown that lipases are even more versatile than thought so far. These results have also prompted workers to rationalize the classification of specificity in terms of substrate promiscuity, condition promiscuity and catalytic promiscuity. The review also attempts to recast the known information on specificity of lipases in the context of enzyme promiscuity. Lipases can exhibit regiospecificity, specificity in terms of fatty acids, nature of the alc., and stereospecificity (distinction between sn-1 and sn-3 position on the triglyceride). Lipases show varied stability toward presence of org. solvents, extreme pH conditions and ionic liqs. In low water media, condition promiscuity in terms of esterification, transesterification and interesterification has been extensively studied. The catalytic promiscuity is being increasingly obsd. for CC bond formation reactions. Finally, the beneficial consequences of this promiscuous behavior in biotechnol. sectors are also discussed.
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    44. 44
      Nguyen, H. D.; Löf, D.; Hvilsted, S.; Daugaard, A. E. Highly branched bio-based unsaturated polyesters by enzymatic polymerization. Polymers 2016, 8, 363  DOI: 10.3390/polym8100363
      44
      Highly branched bio-based unsaturated polyesters by enzymatic polymerization
      Nguyen, Hiep Dinh; Loef, David; Hvilsted, Soeren; Daugaard, Anders Egede
      Polymers (Basel, Switzerland) (2016), 8 (10), 363/1-363/12CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
      A one-pot, enzyme-catalyzed bulk polymn. method for direct prodn. of highly branched polyesters has been developed as an alternative to currently used industrial procedures. Bio-based feed components in the form of glycerol, pentaerythritol, azelaic acid, and tall oil fatty acid (TOFA) were polymd. using an immobilized Candida antarctica lipase B (CALB) and the potential for an enzymic synthesis of alkyds was investigated. The developed method enables the use of both glycerol and also pentaerythritol (for the first time) as the alc. source and was found to be very robust. This allows simple variations in the molar mass and structure of the polyester without premature gelation, thus enabling easy tailoring of the branched polyester structure. The postpolymn. crosslinking of the polyesters illustrates their potential as binders in alkyds. The formed films had good UV stability, very high water contact angles of up to 141°and a glass transition temp. that could be controlled through the feed compn.
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    45. 45
      Wyatt, V. T.; Strahan, G. D. Degree of branching in hyperbranched poly(glycerol-co-diacid)s synthesized in toluene. Polymers 2012, 4, 396– 407,  DOI: 10.3390/polym4010396
      45
      Degree of branching in hyperbranched poly(glycerol-co-diacid)s synthesized in toluene
      Wyatt, Victor T.; Strahan, Gary D.
      Polymers (Basel, Switzerland) (2012), 4 (1), 396-407, 12 pp.CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
      1H NMR and 13C NMR spectrometry (1-dimensional and 2-dimensional) have been used to assign chem. resonances and det. the degrees of branching for polyesters synthesized by the Lewis acid (dibutyltin(IV) oxide)-catalyzed polycondensation of glycerol with either succinic acid [n (aliph. chain length) = 2], glutaric acid (n = 3), or azelaic acid (n = 7) in quasi-melt solns. with toluene. When 1:1 and 2:1 (diacid:glycerol) molar ratios were used, it was found that the glutaric acid-derived polymers gave the highest degree of polymer branching (31.2%, 85.6%, resp.) after the 24 h reaction period followed by the succinic acid-derived polymers (39.4%, 41.9%, resp.), and the azelaic acid-derived polymers (9.9%, 13.9%, resp.). Reactions performed at reflux for 24 h resulted in a 70.8% and 56.7% decrease in degree of branching for succinic acid and glutaric acid-derived polyesters, resp. There is no indication that degree of branching is significantly affected by the presence or absence of solvent according to the results obtained in this research.
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    46. 46
      Holter, D.; Burgath, A.; Frey, H. Degree of branching in hyperbranched polymers. Acta Polym. 1999, 50, 67– 76,  DOI: 10.1002/actp.1997.010480105
      There is no corresponding record for this reference.
    47. 47
      Flory, P. J. Principles of Polymer Chemistry; Cornell University Press: New York, 1953.
      There is no corresponding record for this reference.
    48. 48
      Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 selection guide of classical- and less classical-solvents. Green Chem. 2016, 18, 288– 296,  DOI: 10.1039/C5GC01008J
      48
      CHEM21 selection guide of classical- and less classical-solvents
      Prat, Denis; Wells, Andy; Hayler, John; Sneddon, Helen; McElroy, C. Robert; Abou-Shehada, Sarah; Dunn, Peter J.
      Green Chemistry (2016), 18 (1), 288-296CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      A selection guide of common solvents has been elaborated, based on a survey of publically available solvent selection guides. In order to rank less classical solvents, a set of Safety, Health and Environment criteria is proposed, aligned with the Global Harmonized System (GHS) and European regulations. A methodol. based on a simple combination of these criteria gives an overall preliminary ranking of any solvent. This enables in particular a simplified greenness evaluation of bio-derived solvents.
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    49. 49
      Nijst, C. L. E.; Bruggeman, J. P.; Karp, J. M.; Ferreira, L.; Zumbuehl, A.; Bettinger, C. J.; Langer, R. Synthesis and Characterization of Photocurable Elastomers from Poly(glycerol-co-sebacate). Biomacromolecules 2007, 8, 3067– 3073,  DOI: 10.1021/bm070423u
      49
      Synthesis and Characterization of Photocurable Elastomers from Poly(glycerol-co-sebacate)
      Nijst, Christiaan L. E.; Bruggeman, Joost P.; Karp, Jeffrey M.; Ferreira, Lino; Zumbuehl, Andreas; Bettinger, Christopher J.; Langer, Robert
      Biomacromolecules (2007), 8 (10), 3067-3073CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Elastomeric networks are increasingly being investigated for a variety of biomedical applications including drug delivery and tissue engineering. However, in some cases, their prepn. requires the use of harsh processing conditions (e.g., high temp.), which limits their biomedical application. Herein, we demonstrate the ability to form elastomeric networks from poly(glycerol-co-sebacate) acrylate (PGSA) under mild conditions while preserving a wide range of phys. properties. These networks presented a Young's modulus between 0.05 and 1.38 MPa, an ultimate strength from 0.05 to 0.50 MPa, and elongation at break between 42% and 189% strain, by varying the degree of acrylation (DA) of PGSA. The in vitro enzymic and hydrolytic degrdn. of the polymer networks was dependent on the DA. The copolymn. of poly(ethylene glycol) diacrylate with PGSA allowed for an addnl. control of mech. properties and swelling ratios in an aq. environment, as well as enzymic and hydrolytic degrdn. Photocured PGSA networks demonstrated in vitro biocompatibility as judged by sufficient human primary cell adherence and subsequent proliferation into a confluent monolayer. These photocurable degradable elastomers could have potential application for the encapsulation of temp.-sensitive factors and cells for tissue engineering.
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    50. 50
      Louage, B.; Tack, L.; Wang, Y.; De Geest, B. G. Poly(glycerol sebacate) nanoparticles for encapsulation of hydrophobic anti-cancer drugs. Polym. Chem. 2017, 8, 5033– 5038,  DOI: 10.1039/C6PY02192A
      50
      Poly(glycerol sebacate) nanoparticles for encapsulation of hydrophobic anti-cancer drugs
      Louage, Benoit; Tack, Liesa; Wang, Yadong; De Geest, Bruno G.
      Polymer Chemistry (2017), 8 (34), 5033-5038CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Phys. encapsulation of hydrophobic compds. into nanocarriers that are stable in aq. medium is of high interest as it can increase solubilization of the drug, lower its toxicity, control its pharmacokinetic profile and thus overall improve the therapeutic efficacy. To increase solubilization of a drug in aq. medium, the carrier should contain hydrophobic domains that can form non-covalent interactions with hydrophobic drug mols. Apart from liposomes, polymers have been widely acknowledged as promising nanocarriers. In this paper, we report the design of poly(glycerol sebacate) (PGS), an inexpensive, water insol. but biodegradable and biocompatible polymer, into nanocarriers for hydrophobic drugs. Mixing of alc. PGS solns. with water (i.e. solvent displacement) produced a fine and highly stable dispersion with a size that can be controlled by the PGS concn. and solvent to water ratio. These dispersions were used for the encapsulation of hydrophobic compds. such as a fluorescent dye and two drugs known for their anti-mitotic activity (i.e. paclitaxel (PTX) and flubendazole (FLU)). These formulations were then evaluated in vitro with cancer cells.
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    51. 51
      Laane, C.; Boeren, S.; Vos, K.; Veeger, C. Rules for optimization of biocatalysis in organic solvents. Biotechnol. Bioeng. 1987, 30, 81– 87,  DOI: 10.1002/bit.260300112
      51
      Rules for optimization of biocatalysis in organic solvents
      Laane, Colja; Boeren, Sjef; Vos, Kees; Veeger, Cees
      Biotechnology and Bioengineering (1987), 30 (1), 81-7CODEN: BIBIAU; ISSN:0006-3592.
      General rules for the optimization of different biocatalytic systems in various types of media contg. org. solvents are derived by combining data from the literature, and the logarithm of the partition coeff., log P, as a quant. measure of solvent polarity. Biocatalysis in org. solvents is low in polar solvents having a log P <2, is moderate in solvents having a log P of 2-4, and is high in apolar solvents having a log P >4. This correlation between polarity and activity parallels the ability of org. solvents to distort the essential water layer that stabilizes the biocatalysts. Further optimization of biocatalysis in org. solvents is achieved when the polarity of the microenvironment of the biocatalyst (log Pi) and the continuous org. phase (log Pcph) is tuned to the polarities of both the substrate (log Ps) and the product (log Pp) according to the following rules: |log Pi - log Ps| and |log Pcph- log Pp| should be minimal and |log Pcph - log Ps| and |log Pi - log Pp| should be maximal, with the exception that in the case of substrate inhibition log Pi should be optimized with respect to log Ps. In addn. to these simple optimization rules, the future developments of biocatalysis in org. solvents are discussed.
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    52. 52
      Yao, D.; Li, G.; Kuila, T.; Li, P.; Kim, N. H.; Kim, S.-I.; Lee, J. H. Lipase-Catalyzed Synthesis and Characterization of Biodegradable Polyester Containing L-Malic Acid Unit in Solvent System. J. Appl. Polym. Sci. 2011, 120, 1114– 1120,  DOI: 10.1002/app.33257
      52
      Lipase-catalyzed synthesis and characterization of biodegradable polyester containing L-malic acid unit in solvent system
      Yao, Da-Hu; Li, Guang-Ji; Kuila, Tapas; Li, Peng; Kim, Nam-Hoon; Kim, Seong-Il; Lee, Joong-Hee
      Journal of Applied Polymer Science (2011), 120 (2), 1114-1120CODEN: JAPNAB; ISSN:0021-8995. (John Wiley & Sons, Inc.)
      Lipase-catalyzed direct polycondensation of L-malic acid (L-MA), adipic acid, and 1,8-octanediol in org. media was achieved using Novozym 435 as the biocatalyst. 1H-NMR spectroscopy indicated that the selectivity of Novozym 435 was unaffected by changes in the org. media. The mol. wt. (Mw) of the copolymers was affected by the L-MA feed ratio in the diacids, hydrophobicity of the solvent, and soly. of the substrates in the solvents. The Mw reached a max. of 17.4 kDa at 80°C in isooctane at a L-MA feed ratio in the diacids of 40 mol %. The Mw increased from 3.2 to 16.6 kDa when the reaction time was extended from 6 to 48 h at 70°C, and remained relatively const. with further increases in reaction time from 48 to 72 h. The hydrophilicity, thermal stability, and crystallizability of the copolymer were also investigated. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011.
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    53. 53
      Dutta Banik, S.; Nordblad, M.; Woodley, J. M.; Peters, G. H. A Correlation between the Activity of Candida antarctica Lipase B and Differences in Binding Free Energies of Organic Solvent and Substrate. ACS Catal. 2016, 6, 6350– 6361,  DOI: 10.1021/acscatal.6b02073
      53
      A correlation between the activity of Candida antarctica lipase B and differences in binding free energies of organic solvent and substrate
      Dutta Banik, Sindrila; Nordblad, Mathias; Woodley, John M.; Peters, Gunther H.
      ACS Catalysis (2016), 6 (10), 6350-6361CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      The ability of enzymes to operate in org. solvent is now widely accepted and is the basis for extensive research in enzymol. The challenge is to select the solvent media that allows the modulation of enzyme activity. For a rational selection of a solvent, it is necessary to understand the effect of org. solvent mols. on enzyme structure and the enzymic reaction on a mol. level. Here, to gain such insight, the authors combined exptl. kinetic studies with full at. mol. dynamics simulations and found a correlation between the activity of Candida antarctica lipase B (CALB) [for the esterification reaction between butyric acid and EtOH at a fixed water activity] and the binding of the solvent/substrate mols. in the active site region of CALB. The authors investigated the influence of 4 org. solvents [hexane (HEX), Me tert-Bu ether (MTBE), acetonitrile (ACN), and tert-BuOH (TBU)] on the catalytic activity of CALB for the esterification reaction. The solvents were chosen on the basis of different polarity/functional groups. The study showed that these org. solvents did not alter the overall conformation of CALB; rather, the solvent effects on the performance of the enzyme may be ascribed to binding of solvent mols. to the enzyme active site region and the solvation energy of substrate mols. in the different solvents. Polar solvent mols. interacted strongly with CALB and competed with the substrate to bind to the active site region, resulting in an inhibitory effect which was also confirmed by the binding free energies for the solvent and substrate mols. estd. from the simulations. Consequently, the catalytic activity of CALB decreased in polar solvents. This effect was significant, and CALB was >10 orders of magnitude more active in nonpolar solvents (HEX and MTBE) than in the polar solvents (ACN and TBU). TBU mols. show an exceptional behavior because the solvent mol. formed an extensive H-bond network within the CALB active site region suggesting that solvent mols. rich on H-bond acceptors and donors are poor solvents when used for lipase-catalyzed esterification reactions.
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    54. 54
      Douka, A.; Vouyiouka, S.; Papaspyridi, L. M.; Papaspyrides, C. D. A review on enzymatic polymerization to produce polycondensation polymers: The case of aliphatic polyesters, polyamides and polyesteramides. Prog. Polym. Sci. 2018, 79, 1– 25,  DOI: 10.1016/j.progpolymsci.2017.10.001
      54
      A review on enzymatic polymerization to produce polycondensation polymers: The case of aliphatic polyesters, polyamides and polyesteramides
      Douka, Aliki; Vouyiouka, Stamatina; Papaspyridi, Lefki-Maria; Papaspyrides, Constantine D.
      Progress in Polymer Science (2018), 79 (), 1-25CODEN: PRPSB8; ISSN:0079-6700. (Elsevier Ltd.)
      A review on Enzymic polymn. represents today an effective and preferable alternative to conventional chem.-catalyzed processes. It offers significant advantages, summarized in the applied mild reaction conditions mainly in terms of temp. and toxicity, and high selectivity of enzymes, avoiding protection-deprotection strategies and resulting in improved quality/performance of end products. Esp. for polycondensation polymers, biocatalyzed synthetic routes have been under research for the last thirty years, including homo- and copolymn. of a significant no. of monomers. Aliph. polyesters, polyamides and at a much lower extent polyesteramides, represent the core of the pertinent studies, and are systematically discussed in the current review. Emphasis is given on polycondensates with biodegradability properties, derived from bio-based monomers such as succinic acid, 1,3- propanediol and lactide/lactic acid. Free or immobilized lipases and cutinases are the predominant biocatalysts in the relevant polymer families, being used in polycondensation as well as in ring-opening reaction schemes. The efficiency of the different biocatalytic processes is herein correlated to important process parameters, such as the enzyme and monomer type, the reaction temp. and time, the polymn. technique (soln. or solvent-free), as well as the byproduct removal method, e.g., application of vacuum, water absorption by mol. sieves, azeotropic distn.
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    55. 55
      Distel, K. A.; Zhu, G.; Wang, P. Biocatalysis using an organic-soluble enzyme for the preparation of poly(lactic acid) in organic solvents. Bioresour. Technol. 2005, 96, 617– 623,  DOI: 10.1016/j.biortech.2004.06.005
      55
      Biocatalysis using an organic-soluble enzyme for the preparation of poly(lactic acid) in organic solvents
      Distel, Kelley A.; Zhu, Guangyu; Wang, Ping
      Bioresource Technology (2005), 96 (5), 617-623CODEN: BIRTEB; ISSN:0960-8524. (Elsevier B.V.)
      Proleather from Bacillus sp. was chem. modified with decanoyl chloride for enhanced activity for the prepn. of poly(lactic acid) in org. solvents. The modified enzyme was highly sol. (up to 44 mg-protein/mL) and active in various org. solvents including chloroform, THF (THF), pyridine and acetone. The org.-sol. proleather efficiently catalyzed the polymn. of Et lactate. The reaction rate was 4-22 times that of native proleather, depending upon the solvent applied. The solubilized enzyme showed a highest activity at 50 °C, the same optimum temp. for both the native proleather and an immobilized enzyme, Novozyme-435. Denaturation of the enzymes' protein structures appeared to be the crit. factor regulating the optimum activity temp. Differential scanning calorimetry (DSC) analyses of the enzymes showed endothermic peaks around 55 °C, indicating the proteins' structures altered in that temp. range. Interestingly, the activity of the solubilized enzyme showed a more complicated water dependence as compared to native proleather.
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    56. 56
      Azim, H.; Dekhterman, A.; Jiang, Z.; Gross, R. A. Candida antarctica lipase B-catalyzed synthesis of poly(butylene succinate): Shorter chain building blocks also work. Biomacromolecules 2006, 7, 3093– 3097,  DOI: 10.1021/bm060574h
      56
      Candida antarctica Lipase B-Catalyzed Synthesis of Poly(butylene succinate): Shorter Chain Building Blocks Also Work
      Azim, Himanshu; Dekhterman, Alex; Jiang, Zhaozhong; Gross, Richard A.
      Biomacromolecules (2006), 7 (11), 3093-3097CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Lipase catalysis was successfully employed to synthesize high mol. wt. poly(butylene succinate) (PBS). Attempts to copolymerize succinic acid with 1,4-butanediol were unsuccessful due to phase sepn. of the reactants. To circumvent this problem, monophasic reaction mixts. were prepd. from di-Et succinate and 1,4-butanediol. The reactions were studied in bulk as well as in soln. Of the org. solvents evaluated, di-Ph ether was preferred, giving higher mol. wt. products. After 24 h in di-Ph ether, polymns. at 60, 70, 80, and 90 °C yielded PBS with Mn of 2000, 4000, 8000, and 7000, resp. Further increase in reaction time to 72 h resulted in little or no further increase in Mn. However, increasing the reaction time produced PBS with extraordinarily low Mw/Mn due to the diffusion and reaction between low-mol. wt. oligomers and chains that occurs at a greater frequency than interchain transesterification. Time-course studies and visual observation of polymns. at 80 °C revealed PBS ppts. at 5 to 10 h, limiting the growth of chains. To maintain a monophasic reaction mixt., the polymn. temp. was increased from 80 to 95 °C after 21 h. The result was an increase in the PBS mol. wt. to Mw = 38 000 (Mw/Mn = 1.39). This work paves the way for the synthesis of PBS macromers and polymers that contain variable quantities of monomers with chem. sensitive moieties (e.g., silicone, epoxy, vinyl). Furthermore, this study established the feasibility of using lipase catalysis to prep. polyesters from α,ω-linear aliph. di-Et ester/diol monomers with less than six carbons.
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    57. 57
      Mahapatro, A.; Kumar, A.; Kalra, B.; Gross, R. A. Solvent-free adipic acid/1,8-octanediol condensation polymerizations catalyzed by Candida antartica lipase B. Macromolecules 2004, 37, 35– 40,  DOI: 10.1021/ma025796w
      57
      Solvent-Free Adipic Acid/1,8-Octanediol Condensation Polymerizations Catalyzed by Candida antarctica Lipase B
      Mahapatro, Anil; Kumar, Ajay; Kalra, Bhanu; Gross, Richard A.
      Macromolecules (2004), 37 (1), 35-40CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Bulk condensation polymns. of adipic acid and octanediol, catalyzed by Candida antarctica Lipase B (CALB), were studied. The polymers formed by 8 and 24 h polymns. using CALB immobilized on Accurel and Lewatit had similar mol. wts. (e.g., Mn at 24 h ≈15 000). CALB "free" of the immobilization resin was also active for the polymn. but, relative to its immobilized forms, gave slower chain growth (Mn≈10,000 by 48 h). For all three catalyst systems at d.p. (DP)≥20, dispersity (Mw/Mn) was ≤1.5. Since random processes of step-growth condensation polymns. give dispersity values ≥ 2, the dispersity of products obtained using CALB as the catalyst is believed to result from the unique chain length or mass selectivity of the lipase. Gel permeation chromatograms showed that between 15 min and 4 h chain growth occurred rapidly so that the fraction of product with Mp values > 2910 increased from 28 to 78%. At 70° the catalyst activity at 4 h remained unchanged but decreased by 15 and 21% at 24 and 48 h. Unexpectedly, an increase in the concn. of CALB on Lewatit from 0.1-1% protein resulted in only a small increase in Mn (e.g., at 24 h, 14,500 vs. 17,800). However, decrease in the %protein to 0.5% had a large detrimental effect. Between 65 and 90° the polymns. occurred with little dependence on the reaction temp.
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    58. 58
      Jiang, Y.; Woortman, A. J. J.; Alberda Van Ekenstein, G. O. R.; Loos, K. Environmentally benign synthesis of saturated and unsaturated aliphatic polyesters via enzymatic polymerization of biobased monomers derived from renewable resources. Polym. Chem. 2015, 6, 5451– 5463,  DOI: 10.1039/C5PY00660K
      58
      Environmentally benign synthesis of saturated and unsaturated aliphatic polyesters via enzymatic polymerization of biobased monomers derived from renewable resources
      Jiang, Yi; Woortman, Albert J. J.; Alberda van Ekenstein, Gert O. R.; Loos, Katja
      Polymer Chemistry (2015), 6 (30), 5451-5463CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Aliph. polyesters are of great interest due to their broad potential applications and sustainability. Itaconate-based aliph. polyesters are even more appealing in biomedical and pharmaceutical fields, as they are renewable functional polymers that can be biodegradable, biocompatible, and photo-curable, and might be bioresorbable. Herein, various biobased satd. aliph. polyesters and itaconate-based unsatd. aliph. polyesters are successfully produced via Candida antarctica Lipase B (CALB)-catalyzed polycondensation of (potentially) biobased di-Me itaconate, 1,4-butanediol and various diacid Et esters, using a two-stage method in di-Ph ether. The synthetic aliph. polyesters reach high ‾M‾w (wt. av. mol. wt.) values up to 94 kg mol-1. Studies on the effect of diacid Et esters on the enzymic polymn. reveal that CALB prefers diacid Et esters having a chain length of more than 2 (n > 2, n is the no. of methylene groups between the two carbonyl groups); and CALB shows the highest specificity for di-Et adipate among the tested diacid Et esters (n = 2-10). Moreover, the structure-property relationships are discussed by investigating the chem. structures, cryst. properties and thermal properties of the obtained aliph. polyesters, as well as, the thermal transitions and mech. properties of the UV cross-linked unsatd. polyesters.
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    59. 59
      Kuperkar, V. V.; Lade, V. G.; Prakash, A.; Rathod, V. K. Synthesis of isobutyl propionate using immobilized lipase in a solvent free system: Optimization and kinetic studies. J. Mol. Catal. B: Enzym. 2014, 99, 143– 149,  DOI: 10.1016/j.molcatb.2013.10.024
      59
      Synthesis of isobutyl propionate using immobilized lipase in a solvent free system: Optimization and kinetic studies
      Kuperkar, Vishakha V.; Lade, Vikesh G.; Prakash, Arushi; Rathod, Virendra K.
      Journal of Molecular Catalysis B: Enzymatic (2014), 99 (), 143-149CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
      Iso-Bu propionate is widely used in food and beverage industries as a rum flavor. This work presents the optimization and kinetic aspects of synthesis of iso-Bu propionate by esterification of propionic acid with iso-Bu alc. using immobilized lipase Novozym 435 in a solvent free system (SFS). Process parameters such as reaction time, temp., enzyme loading, speed of agitation, water concn. and acid to alc. molar ratio were optimized to achieve max. conversion. Higher conversion of 92.52% was obtained with the reaction conditions such as: temp. 40°C, enzyme loading 5% wt./wt., acid to alc. molar ratio 1:3, time 10 h and stirring speed of 300 rpm. The bisubstrate kinetic models of the enzyme catalyzed reactions namely Ordered Bi-Bi, Random Bi-Bi and Ping-Pong Bi-Bi were applied to det. the initial rates and correlated with the exptl. findings. Ping-Pong Bi-Bi model with substrate inhibition by both acid and alc. gives the best fit with parameter values as Vmax = 0.5 Mol/min/g catalyst, KA = 0.631 M, KB = 0.003 M, KiA = 0.0042 M and KiB = 0.1539 M for the concn. ranges of 2.25-10.21 M for propionic acid and 2.55-9.01 M for iso-butanol. The immobilized lipase could be reused for seven times with the conversion of acid reaching to 83%; signifies that still it can be reused for several more times. SFS is the added benefit to produce such com. valuable flavor ester.
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    60. 60
      Lopresto, C. G.; Calabrò, V.; Woodley, J. M.; Tufvesson, P. Kinetic study on the enzymatic esterification of octanoic acid and hexanol by immobilized Candida antarctica lipase B. J. Mol. Catal. B: Enzym. 2014, 110, 64– 71,  DOI: 10.1016/j.molcatb.2014.09.011
      60
      Kinetic study on the enzymatic esterification of octanoic acid and hexanol by immobilized Candida antarctica lipase B
      Lopresto, Catia Giovanna; Calabro, Vincenza; Woodley, John M.; Tufvesson, Par
      Journal of Molecular Catalysis B: Enzymatic (2014), 110 (), 64-71CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
      This study investigates reaction kinetics of the esterification of octanoic acid and hexanol into hexyl octanoate, catalyzed by an immobilized Candida antarctica lipase (Novozym 435). The product is considered natural and used as a fresh vegetable and fruity flavor additive in food, cosmetic and pharmaceutical products. The reaction is performed in n-decane as the solvent, to improve enzyme stability and to increase the reaction yield. The influence of substrate concn. on hexyl octanoate synthesis is investigated over a wide range up to 2 M. The obsd. bi-substrate inhibition pattern follows a Ping-Pong bi-bi mechanism with dead-end inhibition by both substrates and, based on the proposed model, the kinetic consts. of the esterification reaction are estd. These parameters are verified to be intrinsic - neither external nor internal mass transfer resistances are significant for the examd. reaction system - and are essential to extend anal. to a large-scale process and for a wide range of operating conditions. The progress of the reaction is also obsd. and the kinetic model is validated by fitting exptl. progress curves with two different concns. of biocatalyst. Effects of biphasicity of the reaction system, inhibition by the ester produced and the influence of the reverse reaction have been also evaluated.
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    61. 61
      Voit, B. I.; Lederer, A. Hyperbranched and Highly Branched Polymer Architectures-Synthetic Strategies and Major Characterization Aspects. Chem. Rev. 2009, 109, 5924– 5973,  DOI: 10.1021/cr900068q
      61
      Hyperbranched and Highly Branched Polymer Architectures-Synthetic Strategies and Major Characterization Aspects
      Voit, Brigitte I.; Lederer, Albena
      Chemical Reviews (Washington, DC, United States) (2009), 109 (11), 5924-5973CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This review has covered the principle synthetic approaches toward hyperbranched polymers as well as various other highly branched polymer architectures developed over the last 20 years.
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    62. 62
      Zhu, X.; Zhou, Y.; Yan, D. Influence of branching architecture on polymer properties. J. Polym. Sci., Part B: Polym. Phys. 2011, 49, 1277– 1286,  DOI: 10.1002/polb.22320
      62
      Influence of branching architecture on polymer properties
      Zhu, Xinyuan; Zhou, Yongfeng; Yan, Deyue
      Journal of Polymer Science, Part B: Polymer Physics (2011), 49 (18), 1277-1286CODEN: JPBPEM; ISSN:0887-6266. (John Wiley & Sons, Inc.)
      A review. Hyperbranched polymers (HBPs), invented at the end of 1980s, are one important subclass of the fourth generation macromol. architectures following the linear, branched, and crosslinking polymers. Due to their unique topol. structure and interesting phys./chem. properties, HBPs have attracted wide attention from both academia and industry. HBPs are composed of linear units, dendritic units, and terminal units. The degree of branching (DB), a term to describe the compn. of these three structure units and thus the branching architecture of polymers, is one of the most important intrinsic parameters for HBPs. This review has summarized the effect of the DB on the phys. and chem. properties of HBPs, including the rheol. property, crystn. and melting behaviors, glass transition, thermal and hydrolytic degrdns., phase characteristics, lower crit. soln. temp. phase transition, optoelectronic properties, encapsulation capability, self-assembly behavior, biomedical applications, and so on. Such a structure and property relationship will build a bridge between the syntheses and applications of HBPs, esp. in the application areas of functional materials, biomedical materials, and nanotechnol. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2011.
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    63. 63
      Murillo, E. A.; Vallejo, P. P.; López, B. L. Characterization of hydroxylated hyperbranched polyesters of fourth and fifth generation. e-Polymers 2010, 10, 1347– 1358,  DOI: 10.1515/epoly.2010.10.1.1347
      There is no corresponding record for this reference.
    64. 64
      Xiang, F.; Stuart, M.; Vorenkamp, J.; Roest, S.; Timmer-Bosscha, H.; Stuart, M. C.; Fokkink, R.; Loontjens, T. One-pot synthesis for biocompatible amphiphilic hyperbranched polyurea micelles. Macromolecules 2013, 46, 4418– 4425,  DOI: 10.1021/ma400552x
      64
      One-Pot Synthesis for Biocompatible Amphiphilic Hyperbranched Polyurea Micelles
      Xiang, Fei; Stuart, Marc; Vorenkamp, Joop; Roest, Steven; Timmer-Bosscha, Hetty; Stuart, Martien Cohen; Fokkink, Remco; Loontjens, Ton
      Macromolecules (Washington, DC, United States) (2013), 46 (11), 4418-4425CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Here we report, for the first time to our knowledge, a method to synthesize AB2 monomers, the corresponding hyperbranched and the corresponding amphiphilic hyperbranched polymers in a one-pot procedure, starting from two com. available compds. Since the B groups were blocked isocyanates (BIs), the end groups of the hyperbranched polyurea were BIs as well. Coupling of a range of monomethoxy-poly(ethylene glycol)s onto the BIs yielded a platform of amphiphilic hyperbranched polymers, with controllable hydrophobic cores and hydrophilic shells. After the three consecutive reaction steps, without intermediate purifn., the final polymers were purified by pptn. in a nonsolvent, in which the polymer pptd. and the excess PEG remained dissolved. Pyrene inclusion expts. showed the formation of micelles above a crit. concn. Both cryo-EM and DLS revealed the presence of two distinct particle populations, being the primary micelles and aggregates thereof. All micelles showed a LCST behavior, with transitions close to body temp. The low cytotoxicity of the micelles make them promising for drug delivery.
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    65. 65
      Žagar, E.; Grdadolnik, J. An infrared spectroscopic study of H-bond network in hyperbranched polyester polyol. J. Mol. Struct. 2003, 658, 143– 152,  DOI: 10.1016/S0022-2860(03)00286-2
      65
      An infrared spectroscopic study of H-bond network in hyperbranched polyester polyol
      Zagar, Ema; Grdadolnik, Joze
      Journal of Molecular Structure (2003), 658 (3), 143-152CODEN: JMOSB4; ISSN:0022-2860. (Elsevier Science B.V.)
      A FTIR study of aliph. hyperbranched polyester of the fourth generation Boltorn H40 (BH40) is presented. In order to properly assign the main vibrational bands in IR spectrum temp. measurements, hydration and H/D exchange expts. were performed. Beside these expts., difference spectroscopy, 2D generalized correlation IR spectroscopy (2-DGCS) and band fitting procedure were employed to study the main interactions in polymer. On the basis of the detected interactions between various groups the structure of a H-bond network in hyperbranched polyester is proposed. Three main H-bond interactions were detected. Besides C:O···HO and HO···HO a third type of H-bond is present (C:O···HO···HO). A minor type of interactions represent the hydrogen bond formed with the carboxyl COOH group and impurities, which may be present in lower concn.
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    66. 66
      Godinho, B.; Gama, N.; Barros-Timmons, A.; Ferreira, A. Enzymatic synthesis of poly(glycerol sebacate) pre-polymer with crude glycerol, by-product from biodiesel prodution. AIP Conf. Proc. 2018, 1981, 020031  DOI: 10.1063/1.5045893
      66
      Enzymatic synthesis of poly(glycerol sebacate) pre-polymer with crude glycerol, by-product from biodiesel prodution
      Godinho, Bruno; Gama, Nuno; Barros-Timmons, Ana; Ferreira, Artur
      AIP Conference Proceedings (2018), 1981 (1, International Conference on "Times of Polymers and Composites", 2018), 020031/1-020031/4CODEN: APCPCS; ISSN:0094-243X. (American Institute of Physics)
      The biodiesel fuel technol. has attracted researchers worldwide as a viable alternative to fossil fuel consumption. The biodiesel prodn. increment has resulted in a severe waste disposal crisis, because to produce 10 Kg of biodiesel, around 1 Kg of crude glycerol is produced. Therefore, it is essential to find valuable applications for this byproduct. The biodegradable polymers have attracted interest, since many of their building blocks can be obtained from renewable sources. Poly(glycerol sebacate) (PGS) is polyester elastomer with potential biomedical applications, such, the recovery of soft tissues and organs and the delivery of pharmaceutical drugs. In this study, we report the successful synthesis of pre-polymer of PGS with Candida antarctica lipase B free (CALB) and lipase B immobilized Novozym 435 (N435) with crude glycerol and pure glycerol. The pre-polymers were analyzed by mass spectrometry MALDI-Tof-MS and RMN. (c) 2018 American Institute of Physics.
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    67. 67
      Brandner, J. D.; Birkmeier, R. L. Relative esterifiability of the primary and secondary hydroxyl groups of glycerol. J. Am. Oil Chem. Soc. 1960, 37, 390– 396,  DOI: 10.1007/BF02672644
      67
      Relative esterifiability of the primary and secondary hydroxyl groups of glycerol
      Brandner, J. D.; Birkmeier, R. L.
      Journal of the American Oil Chemists' Society (1960), 37 (), 390-6CODEN: JAOCA7; ISSN:0003-021X.
      The 2 assumptions on predicting distribution of acyl groups of Feuge and Bailey (CA 40, 62731) (a) that there is equal chance of esterification of -OH groups and (b) that there is no formation of β-monoglyceride, are re.ovrddot.examd. A test on the course of esterification of ethylene glycol with oleic acid demonstrated equal and independent activity of the primary -OH groups. This data is interpreted that it is reasonable to expect this to be true of the primary -OH groups of glycerol. Math. analyses of data from literature and by B. and B. on esterification of glycerol showed that, contrary to Feuge and Bailey, the primary and secondary -OH groups are not equally esterifiable. The equil. const. favoring esterification of primary -OH over secondary is about 2.3 at reaction temp. Since the equil. const. is substantially different at room temp. from that at reaction temp., monoglycerides as customarily prepd. are not at equil. at room temp. and undergo intramol. migration of acyl groups from β- to α-OH positions. The rate of migration depends on the phys. form of the ester and is accelerated by basic catalysts. At room temp., intermol. rearrangement occurs only over very prolonged periods. The method of calcg. relative esterifiability of primary and secondary -OH groups should be applicable to other polyols.
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    68. 68
      Serdarevich, B. Glyceride isomerizations in lipid chemistry. J. Am. Oil Chem. Soc. 1967, 44, 381– 393,  DOI: 10.1007/BF02666775
      68
      Glyceride isomerizations in lipid chemistry
      Serdarevich, B.
      Journal of the American Oil Chemists' Society (1967), 44 (7), 381-93CODEN: JAOCA7; ISSN:0003-021X.
      Acetal and ketal isomerizations in glycerides with isopropylidene and benzylidene blocking groups, and acyl migration (intramol. transesterification) in esters of carboxylic acids and H3PO4 which pose difficulties in prepn., isolation, and characterization of lipids are studied. Reaction of PhCHO with glycerol gave 4 benzylideneglycerol isomers (cis-1,2-, trans-1,2-, cis-1,3-, trans-1,3-) which were sepd. by column chromatog. and characterized by N.M.R. spectroscopy and other methods. With mono- and diglycerides having ester groups in the 2-position, the driving force in isomerization is elimination of the steric effect of branching (2-position), by conversion to stable linear forms (1-monoglycerides or 1,3-diglycerides). A slower acyl migration in diglycerides compared to monoglyceride is attributed to slower formation of the transition state ring-intermediate. In all cases ratio of isomers in isomerized products are reported. Similar data are reported for 1- and 2-glyceryl phosphates and of cyclic glyceryl phosphates by acid and base isomerization. Hydrolysis products of L-3-glycerylphosphorylcholine and 2-glycerylphosphorylcholine were sepd. by column chromatog. and characterized by periodic acid oxidn., optical rotation, and N.M.R. spectroscopy. No isomerization of unhydrolyzed L-3-glycerylphosphorylcholine and 2-glycerylphosphorylcholine was observed. Evidence indicated that acid-catalyzed hydrolyses of phosphoglycerides are under thermodynamic control whereas most basecatalyzed hydrolyses are under kinetic control. 93 references.
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    69. 69
      Mao, J.; Hu, Z.; Hu, J.; Zhu, X.; Xiong, H. A Density Functional Theory (DFT) study of the Acyl migration occurring during lipase-catalyzed transesterifications. Int. J. Mol. Sci. 2019, 20, 3438  DOI: 10.3390/ijms20143438
      69
      A density functional theory (DFT) study of the acyl migration occurring during lipase-catalyzed transesterifications
      Mao, Jinyuan; Hu, Zhenying; Hu, Jiangning; Zhu, Xuemei; Xiong, Hua
      International Journal of Molecular Sciences (2019), 20 (14), 3438pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      Acyl migration (AM) is the main side reaction in the large-scale, regio-specific lipase catalyzed prodn. of structural triglycerides (STs). A detailed understanding of the mechanism of AM was obtained during the process of lipase-catalyzed schemes (LCSs), which play a vital role in improving the quality and total yield of STs. However, currently, the mechanism of AM remains controversial. Herein, the two mechanisms (non-catalyzed (NCM) and lipase-catalyzed (LCM)) of AM have been analyzed in detail by the d. functional theory (DFT) at the mol. level. Based on the computational results, we concluded that the energy barrier of the rate-limiting step in the LCM was 18.8 kcal/mol, which is more in agreement with the available exptl. value (17.8 kcal/mol), indicating that LCM could significantly accelerate the rate of AM, because it has an energy barrier ∼2 times lower than that of the NCM. Interestingly, we also found that the catalytic triad (Asp-His-Ser) of the lipase and water could effectively drop the reaction barrier, which served as the general acid or base, or shuttle of the proton.
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    70. 70
      Xu, X.; Skands, A. R. H.; Høy, C. E.; Mu, H.; Balchen, S.; Adler-Nissen, J. Production of specific-structured lipids by enzymatic interesterification: Elucidation of acyl migration by response surface design. J. Am. Oil Chem. Soc. 1998, 75, 1179– 1186,  DOI: 10.1007/s11746-998-0132-6
      70
      Production of specific-structured lipids by enzymic interesterification: elucidation of acyl migration by response surface design
      Xu, X.; Skands, A. R. H.; Hoy, C.-E.; Mu, H.; Balchen, S.; Adler-Nissen, J.
      Journal of the American Oil Chemists' Society (1998), 75 (9), 1179-1186CODEN: JAOCA7; ISSN:0003-021X. (AOCS Press)
      Prodn. of specific-structured lipids (SSL) by lipase-catalyzed interesterification has been attracting more and more attention recently. However, it was found that acyl migration occurs during the reaction and causes the prodn. of byproducts. In this paper, the elucidation of acyl migration by response surface design was carried out in the Lipozyme IM (Rhizomucor miehei)-catalyzed interesterification between rapeseed oil and capric acid in solvent-free media. A five-factor response surface design was used to evaluate the influence of five major factors and their relationships. The five factors, water content, reaction temp., enzyme load, reaction time and substrate ratio, were varied at three levels together with two star points. All parameters besides substrate ratio had strong pos. influences on acyl migration, and reaction temp. was most significant. The contour plots clearly show the interactions between the parameters. The migration rates of different fatty acids were also compared from three different sets of expts. during the lipase-catalyzed reaction. The best-fitting quadratic response surface model was detd. by regression and backward elimination. The coeffs. of detn. (R2) of the model were 0.996 and 0.981 for Q2 value. The results show that the fitted quadratic model satisfactorily expresses acyl migration for the enzymic interesterification in the batch reactor used.
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    71. 71
      Laszlo, J. A.; Compton, D. L.; Vermillion, K. E. Acyl migration kinetics of vegetable oil 1,2-diacylglycerols. J. Am. Oil Chem. Soc. 2008, 85, 307– 312,  DOI: 10.1007/s11746-008-1202-5
      71
      Acyl migration kinetics of vegetable oil 1,2-diacylglycerols
      Laszlo, Joseph A.; Compton, David L.; Vermillion, Karl E.
      Journal of the American Oil Chemists' Society (2008), 85 (4), 307-312CODEN: JAOCA7; ISSN:0003-021X. (Springer)
      The acyl migration kinetics of long-chain 1,2-diacylglycerol (1,2-DAG) to form 1,3-diacylglycerol (1,3-DAG) over the temp. range of 25-80 °C were examd. using 1H-NMR spectroscopy. Lipase-catalyzed propanolysis of high-oleic sunflower oil, followed by a series of solvent extn. steps, generated high purity 1,2-DAG (0.93 mol fraction of the DAG content). The 1,2-DAG mole fraction of 0.32 at equil. was found to be insensitive to temp., indicating that long-chain acyl group migration is neither endothermic nor exothermic. Detn. of the temp.-dependent, first-order reaction kinetic parameters revealed a 1,2-DAG half life (t1/2) of 3,425 h and 15.8 h at 25 and 80 °C, resp. A comparison of 1,2-DAG with 2-monoacylglycerol indicated that there is no difference between the two in the potential energy state (ΔG‡) of their resp. transitions states or cyclic intermediates.
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    72. 72
      Compton, D. L.; Vermillion, K. E.; Laszlo, J. A. Acyl migration kinetics of 2-Monoacylglycerols from soybean oil via 1H NMR. J. Am. Oil Chem. Soc. 2007, 84, 343– 348,  DOI: 10.1007/s11746-007-1049-1
      72
      Acyl migration kinetics of 2-monoacylglycerols from soybean oil via 1H NMR
      Compton, David L.; Vermillion, Karl E.; Laszlo, Joseph A.
      Journal of the American Oil Chemists' Society (2007), 84 (4), 343-348CODEN: JAOCA7; ISSN:0003-021X. (Springer)
      The acyl migration kinetics of neat 2-monoacylglycerol (2-MAG) to form 1-MAG was detd. using 1H NMR spectroscopy to monitor the β-proton integration ratios of the two species over time. 2-MAG was synthesized by the Novozym 435-catalyzed alcoholysis of soybean oil and isolated by solvent extn. or mol. distn. at a mole fraction (X2-MAG) of 0.94 relative to total MAG. The kinetics parameters of the neat 2-MAG acyl migration were investigated over the temp. range of 23-80°. The 2-MAG mol. fraction remained unchanged at 23° over the course of 168 h and reached an equil. of X2-MAG = 0.09 at only 80°. Modeling of the kinetics data revealed a 2-MAG half life (t1/2) of 3,500 and 22.8 h at 23 and 80°, resp., with an activation energy of 79.0±6.5 kJ mol-1. The use of 1H NMR spectroscopy proved an expedient method for monitoring the acyl migration in 2-MAG compared to other reported methods (e.g. GC, HPLC, and 13C-NMR spectroscopy), requiring no sample manipulation and minimizing the deleterious effects of high temps. and solvent exposure.
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    73. 73
      Li, W.; Du, W.; Li, Q.; Li, R.-w.; Liu, D. Dependence on the properties of organic solvent: Study on acyl migration kinetics of partial glycerides. Bioresour. Technol. 2010, 101, 5737– 5742,  DOI: 10.1016/j.biortech.2010.03.018
      73
      Dependence on the properties of organic solvent: Study on acyl migration kinetics of partial glycerides
      Li, Wei; Du, Wei; Li, Qiang; Li, Ren-wang; Liu, Dehua
      Bioresource Technology (2010), 101 (15), 5737-5742CODEN: BIRTEB; ISSN:0960-8524. (Elsevier Ltd.)
      During Rhizopus oryzae-mediated methanolysis of triglycerides for biodiesel prodn., the amt. of 1,2-DG and 2-MG as well as the ratio of 1,2-DG/1,3-DG and 2-MG/1-MG differed significantly in different reaction medium, which indicated that solvent might be a crucial factor that would influence the acyl migration rate, leading to varied biodiesel yield. The influence of solvent and their properties on acyl migration kinetics of both 1,2-diglyceride and 2-monoglyceride were studied systematically. Decreasing solvent polarity would give increasing acyl migration rate consts. in general. Solvent polarity influenced the acyl migration rate through the influence of the charge dispersion of the transition state. High polarity of the solvent was unfavorable to the transition state charge dispersion, which would increase its energy state, and thus decreased the acyl migration rate and then led to relatively lower Me ester yield.
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    74. 74
      Li, W.; Du, W.; Li, Q.; Sun, T.; Liu, D. Study on acyl migration kinetics of partial glycerides: Dependence on temperature and water activity. J. Mol. Catal. B: Enzym. 2010, 63, 17– 22,  DOI: 10.1016/j.molcatb.2009.11.012
      74
      Study on acyl migration kinetics of partial glycerides: Dependence on temperature and water activity
      Li, Wei; Du, Wei; Li, Qiang; Sun, Ting; Liu, De-Hua
      Journal of Molecular Catalysis B: Enzymatic (2010), 63 (1-2), 17-22CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
      Acyl migration phenomenon was often obsd. during 1,3-positional specificity lipase-catalyzed reactions from triglycerides and partial glycerides, including acyl migration of 1,2-diglyceride (1,2-DG) to 1,3-diglyceride (1,3-DG) and 2-monoglyceride (2-MG) to 1-monoglyceride (1-MG). However, the acyl migration mechanism and kinetics were seldom studied despite numerous researches on process optimization of 1,3-positional specificity lipase-catalyzed reaction. In this paper, the influence of related factors on acyl migration process as well as their influencing mechanism was further studied. It was found that temp. and water activity were two crucial factors that would influence acyl migration kinetics. Detn. of the kinetic parameters under different temps. revealed that the acyl migration reaction rates were greatly promoted by the increasing of temp. The acyl migration rates of 1,2-diglyceride and 2-monoglyceride were quite different from each other, which was found to be due to the different activation energies. Further study of how would water influence the acyl migration process showed that water activity rather than water content was a key factor that influenced acyl migration and the acyl migration rate would decrease with the increase of water activity. It was further revealed that water activity influenced the charge dispersion of the transition state, which ultimately influenced the reaction activation energy and then influenced the acyl migration rate.
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    75. 75
      Fureby, A. M.; Virto, C.; Adlercreutz, P.; Mattiasson, B. Acyl group migrations in 2-monoolein. Biocatal. Biotransform. 1996, 14, 89– 111,  DOI: 10.3109/10242429609106879
      75
      Acyl group migrations in 2-monoolein
      Fureby, Anna Millqvist; Virto, Carmen; Adlercreutz, Patrick; Mattiasson, Bo
      Biocatalysis and Biotransformation (1996), 14 (2), 89-111CODEN: BOBOEQ; ISSN:1024-2422. (Harwood)
      Acyl migration in 2-monoolein dissolved in solvents under conditions common in lipid modification reactions has been studied. The effects on acyl migration of solvent, incubation temp., water activity, polar additives and solid additives have been investigated. Extensive acyl migration occurred in aliph. hydrocarbons and water-miscible alcs. under dry conditions. The acyl migration rate could be decreased in several nonpolar solvents by adding a small amt. of water or an alc. Increasing water activity had no effect in isooctane, but decreased the acyl migration rate dramatically in Me tert-Bu ether and Me iso-Bu ketone. Several commonly used enzyme supports catalyzed acyl migration, showing that supports with surface charges could catalyze acyl migration.
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    76. 76
      Freeman, I. P.; Morton, D. Acyl Migration in Diglycerides. J. Chem. Soc. C 1966, 1710– 1711,  DOI: 10.1039/J39660001710
      76
      Acyl migration in diglycerides
      Freeman, I. P.; Morton, I. D.
      Journal of the Chemical Society [Section] C: Organic (1966), (19), 1710-11CODEN: JSOOAX; ISSN:0022-4952.
      The equil. between 1,2-dipalmitin and 1, 3-dipalmitin as a result of acyl migration has been studied using thin-layer chromatography and densitometry. When isomerization is catalyzed by KOH, the composition of the equil. mixt. varies with the temp. of the isomerization. This variation is consistent with the idea that the equil. compn. is a function of the relative rates of esterification of primary and secondary OH groups.
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    77. 77
      Li, W.; Li, R. W.; Li, Q.; Du, W.; Liu, D. Acyl migration and kinetics study of 1(3)-positional specific lipase of Rhizopus oryzae-catalyzed methanolysis of triglyceride for biodiesel production. Process Biochem. 2010, 45, 1888– 1893,  DOI: 10.1016/j.procbio.2010.03.034
      77
      Acyl migration and kinetics study of 1(3)-positional specific lipase of Rhizopus oryzae-catalyzed methanolysis of triglyceride for biodiesel production
      Li, Wei; Li, Ren-wang; Li, Qiang; Du, Wei; Liu, Dehua
      Process Biochemistry (Amsterdam, Netherlands) (2010), 45 (12), 1888-1893CODEN: PBCHE5; ISSN:1359-5113. (Elsevier B.V.)
      The lipase of Rhizopus oryzae (R. oryzae) was reported to have 1(3)-positional specificity, but in the process of R. oryzae-catalyzed biodiesel prodn., the yield of biodiesel (Me esters) could reach over 80%. Although during 1(3)-positional specific lipase-catalyzed methanolysis of triglycerides, acyl migration was thought as one of the major reasons for higher Me ester yield, there was no further study on the mechanism exploration regarding to acyl migration. In this paper, acyl migration and the related kinetics of R. oryzae-mediated methanolysis of triolein was studied systematically. Through our study, it was revealed that during the methanolysis process, acyl migration between 2-MG and 1-MG as well as acyl migration between 1,2-DG and 1,3-DG could take place independent of enzymic catalysis. The kinetic study showed that the acyl migration was first-order reversible reaction. Based on this finding, a two-step mechanic model including acyl migration was developed for the enzyme-mediated methanolysis for biodiesel prodn. and it was found that the reaction included consecutive hydrolysis and esterification. Further investigation on kinetics showed that R. oryzae lipase was not restrict selectivity of 1(3)-position acyl group, but a preference of 1(3)-position over 2-position, which also contributed to the higher yield of Me esters.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.macromol.0c01709.

    • Summarized polycondensation conditions and characteristics of glycerol-based polyesters prepared via CALB catalysis, IR spectrum, 13C NMR spectrum, 1H–13C HSQC contour map, 1H–1H COSY contour map, temporal evolution of 1H NMR spectra signals, 1H NMR curve-fitted signals of methylene protons adjacent to the sebacic acid/ester carbonyl, structural parameters calculations, comparison of results from 1H NMR and quantitative 13C NMR, general data from the 1H NMR and GPC analyses, DLS analyses and CAC estimation, x1T/x2T and x1,3L/x1,2L molar fraction ratio as a function of time, and acyl migration experiment (PDF)


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