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Chemoselective Acetylation of 2‑Aminophenol Using Immobilized Lipase: Process Optimization, Mechanism, and Kinetics Deepali B. Magadum† and Ganapati D. Yadav*,† †
Department of Chemical Engineering, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400 019, India
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S Supporting Information *
ABSTRACT: N-(2-Hydroxyphenyl)acetamide is an intermediate for the complete natural synthesis of antimalarial drugs. Chemoselective monoacetylation of the amino group of 2-aminophenol to N-(2-hydroxyphenyl)acetamide was carried out by employing Novozym 435 as the catalyst. Different acyl donors such as vinyl acetate, vinyl butyrate, acetic anhydride, and ethyl acetate were studied. The effect of various parameters such as different acyl donors, speed of agitation, solvent, catalyst loading, mole ratio, and temperature was studied. Vinyl acetate was found to be the best acyl donor among the studied acyl donors since it leads to an irreversible reaction. It is a kinetically controlled synthesis since vinyl acetate was used as the activated acyl donor. The substrate to acyl donor ratio was 1:3. The mechanism for the given reaction system was predicted based on the observations of Lineweaver− Burk plots. It was observed that the reaction followed a ternary complex model with inhibition by vinyl acetate, and kinetic constants were estimated using the Polymath 6.0 software. Under the final optimized conditions, the conversion for the reaction was found to be 74.6% in 10 h.
1. INTRODUCTION The frontiers of sustainability are vigorously driving the application of enzymes to large-scale synthesis of fine and pharmaceutical chemicals.1 Enzymes have made inroads as industrial biocatalysts because they are enormously selective and specific, catalyze reactions at very mild temperatures and pressures, and in nonaqueous and aqueous reaction media.1−3 The key advantages of enzymatic transformation are selectivity toward a single product, working under milder conditions, reduction in the cost of purification and environmental sustainability.1−3 Along with the enantioselective nature of biocatalysts, the chemoselective attribute of enzymes is also extensively explored for the synthesis of biomolecules. Lipases are a major class of enzymes because of their unique properties, such as the absence of a cofactor, wide range of working solvents, recognition of chiral centers, and substrate specificity. Immobilization of enzymes by different protocols has been employed to increase the activity, specificity, selectivity, inhibitor-resistance, etc. through a proper selection of support and procedure for immobilization.4,5 Immobilization of enzymes may lead to changes in activity, specificity, or selectivity. In several instances, distortion in enzyme properties is observed due to immobilization because of the interaction with the support, whereas in some cases such properties may be improved by the immobilization on an appropriate support.5 Interfacial activation of lipases occurs on hydrophobic supports at low ionic strength. This immobilization technique is able to immobilize lipases through the hydrophobic surroundings of their active center thereby fixing their open conformation.6,7 Chemoselective monoacetylation using lipase as a catalyst is a suitable approach in the synthesis of enantiomerically pure diols © 2018 American Chemical Society
by sequential kinetic resolution of monoacylated derivatives.8−15 Various selective reactions have been reported by using lipase as a catalyst for a range of substrates, such as 3aryloxy-1,2-propanediols, fatty acids, derivatives of galactopyranosides, pyridoxine, dicaprin, tetrol, and triolein.8−16 Amidation of aniline and formation of a Mannich base was carried out using lipase as a catalyst.13,14 To explore the complete potential, the promiscuous nature of lipase can be explored by varying the source of lipase-producing bacteria or fungi.1−3 This makes lipase a suitable catalyst for the synthesis of a range of chemicals. As stated earlier, immobilization offers many advantages, including different configurations of reactors including flow reactors, resistance to chemicals, lower inhibition, modulation of selectivity or specificity, and also purification, which have been reviewed from time to time, and immobilized enzymes can be explored for industrial-level production.8,17−21 Novozym 435 is a Cal B lipase immobilized on a hydrophobic carrier, i.e., an acrylic resin.22 It provides added advantages such as being mild and selective on multifunctional substrates, performs well under anhydrous conditions and on moisturesensitive substrates, and works well in batch and continuous fed batch reactors over a wide range of temperatures (20−110 °C).16,23−26 The changes in enzyme properties upon immobilization are related to structural changes in the enzyme. For lipases such as Cal B immobilized on hydrophobic supports, there is stabilization of the hyperactivated lipase form via interfacial activation.4 It is reported that lipases such as Cal B Received: June 23, 2018 Accepted: December 13, 2018 Published: December 27, 2018 18528
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as well as it leads to a change in the pH of the reaction medium. Therefore, vinyl butyrate led to lower conversion (∼20.2%) with reference to vinyl acetate (Figure 1). Second, it also creates steric
exist in open and closed forms in aqueous media. During interfacial activation, the close lid is opened and the active center becomes exposed to the medium.27−29 The open form of the lipases is adsorbed through the huge hydrophobic pocket exposed to the hydrophobic surface. This is the so-called interfacial activation of lipases.29 N-(2-Hydroxyphenyl)acetamide is used as an intermediate for the complete natural synthesis of antimalarial products.30 N(2-Hydroxyphenyl)acetamide showed anti-arthritic and antiinflammatory activities. It also reduced oxidative stress markers with relevance to its anti-inflammatory activity.31 It can be synthesized using various organic reagents such as N-acyl-N-(4chlorophenyl)-4-nitrobenzenesulfonamides, stannous chloride, chloroamine, and trifluroacetic acids.32−34 Different catalysts such as chitosan-supported Zn mixed ligands, Keggin-type Brønsted dodecatungstophosphoric acid and doped silica gel complexes, and supported solid acids are used in the single-pot production of amides from ketone via a Beckmann rearrangement.35−38 The solid acid catalyst and silver nanoparticle embedded mesoporous polyaniline nanocomposites were also explored for the synthesis of acylated aniline and other amino alcohols.34,39 This type of rearrangement can be carried out with self-catalyzed direct amidation of ketone.40 Copper oxide nanoparticles in water were applied for the synthesis of benzoxazoles and o-hydroxyanilides.41 It can also be synthesized directly using hydroquinone or with whole cell catalysis using Fusarium verticillioides. In this work, we have devised a method for chemoselective synthesis of N-(2-hydroxyphenyl)acetamide using immobilized lipase in nonaqueous media under milder conditions. The study focuses on the sustainable development and optimization of the chemoselective acetylation process, including the mechanism and kinetic model for the synthesis of N-(2-hydroxyphenyl)acetamide (Scheme 1).
Figure 1. Effect of acyl donors. (Reaction condition: 2-aminophenol = 1.0 mmol, acyl donor = 3.0 mmol, T = 50 °C, tetrahydrofuran (THF) up to 10 mL, Novozym 435 = 0.003 g/mL, speed of agitation = 250 rpm, time = 10 h.)
hindrance in the active site of the lipase and shows less conversion compared to vinyl acetate. When ethyl acetate and acetic anhydride undergo transesterification, ethanol and acetic acid are released as co-products.43,44 Ethanol might act as a nucleophile, whereas acetic acid release leads to a change in the pH of the reaction mixture. This resulted in a lower conversion of 28.5% for ethyl acetate and 40.7% for acetic anhydride. This is a kinetically controlled reaction based on the use of an activated acyl donor vinyl ester to achieve maximum transient yields that are dependent on the interplay of three different reactions simultaneously catalyzed by the enzyme, namely, (a) the final product formation, (b) hydrolysis of the activated acyl donor, and (c) the final product hydrolysis.4,45 Immobilized enzyme activity in a kinetically controlled reaction is dependent on the adsorption of the substrate on the active center of the lipase, the specificity of the lipase versus the active acyl donor (vinyl acetate) and the product, N-(2-hydroxyphenyl)acetamide. All of these three processes depend on the type of lipase and will be profoundly modulated by the enzyme structure after immobilization on the support.45−48 Therefore, vinyl acetate was utilized as the acyl donor in further studies. 2.2. Effect of Different Solvents. The functional groups and polarity of the medium impact the selectivity and activity of the lipases. The logarithmic value of the partition coefficient (log P) is a measure of hydrophobicity or hydrophilicity. Enhanced solubility of the reactant in the medium increases its accessibility to the active site of the lipase without disturbing water activity. The lipase showed optimum activity in a nonpolar solvent (log P > 4), and a mid-polar solvent (2 < log P < 4) maintained the activity of the lipase compared with polar solvents.35,38,39 The results of effect of solvents such as tert-butyl alcohol (t-BA) (log P = 0.584), tetrahydrofuran (log P = 0.59),
Scheme 1. Chemoselective Acetylation of 2-Aminophenol Using Novozym 435
2. RESULTS AND DISCUSSION 2.1. Effect of Different Acyl Donors. The acyl donor influences the rate and selectivity of a reaction. The conversion is inversely proportional to the chain length or size of the group attached.25,26,42 Various acyl donors such as vinyl acetate, vinyl butyrate, acetic anhydride, and ethyl acetate were studied. Using vinyl acetate as the acyl group donor led to the formation of vinyl alcohol. The equilibrium of the reaction was disturbed as the liberated co-product, vinyl alcohol, was instantaneously tautomerized to form acetaldehyde. Furthermore, as acetaldehyde has a low boiling point of 20 °C, it escaped the reaction mass leading to irreversibility. This did not allow the reaction to be reversible and enhanced the yield of the reaction. Therefore, the conversion was very high (52%) in comparison with others. Employing other vinyl donors was not effective. For instance, use of vinyl butyrate as the acyl donor releases butyric acid, which remains in the system and makes the reaction reversible, 18529
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dimethylformamide (DMF) (log P = −0.829), and 1,4-dioxane (log P = 0.03) are in line with the findings in the literature. Novozym 435 showed 3.7 and 40% conversion for DMF and 1,4-dioxane, respectively. In the polar medium, the necessary water layer around the lipase gets disturbed, and the activity of the lipase drops significantly. The conversion was 84 and 52% for tert-butanol and THF, respectively. Even though the use of tert-butanol gave the highest conversion during the reaction, the catalyst led to complete acetylation of 2-aminophenol, which decreases the selectivity of the reaction. Hence, further studies were carried out in THF (Figure 2).
Figure 3. Effect of speed of agitation. (Reaction condition: 2aminophenol = 1.0 mmol, vinyl acetate = 3.0 mmol, T = 50 °C, THF up to 10 mL, Novozym 435 = 0.003 g/mL, speed of agitation = 150− 300 rpm, time = 10 h.)
Figure 2. Effect of solvents. (Reaction condition: 2-aminophenol = 1.0 mmol, vinyl acetate = 3.0 mmol, T = 50 °C, solvent up to 10 mL, Novozym 435 = 0.003 g/mL, speed of agitation = 250 rpm, time = 10 h.)
as the rate of diffusion is higher than the reaction rate per unit area. Hence, 250 rpm was selected as the optimal speed of agitation. 2.4. Effect of Catalyst Loading. The experiments were designed in the range of 0.67−6.67 mg/cm3 of catalyst loading to study its influence on the rate of reaction (Figure 4). The plot of the initial rate of reaction versus catalyst loading showed direct proportion (figure not shown for the sake of brevity). The available number of active sites in the reaction mixture increases with increase in catalyst charging. The initial rate with catalyst loading 4.67 and 6.67 mg/cm3 hardly differs for the reaction. The number of active sites available at 6.67 mg/cm3 far exceeded
2.3. Effect of Speed of Agitation. The substrate interacts with the catalytic site of the lipase after crossing the bulk liquid, to form a particle−surface interface. The complete agitation of the reaction mixture led to elimination of external mass transfer resistance.40 The study was planned by varying the speed of agitation in the range of 100−300 rpm (Figure 3). The experiments at 150 and 200 rpm exhibited a low initial reaction rate with 24.8 and 34.7% conversion. At 250 rpm, the initial reaction rate showed no significant difference from that at 300 rpm with a conversion of 52%. At 250 rpm and above, the mass transfer resistance was eliminated and hence, it was taken as the optimized speed of agitation. The time constants of the reaction (tr) and diffusivity (td) are evaluated for the influence of mass transfer resistance in the reaction system.41,42 The values of td and tr were calculated to be 1.106 × 10−3 and 24.25 s, respectively. The value of tr was greater than that of td, as the external mass transfer resistance was completely removed from the reaction. Intraparticle mass diffusion limitation was analyzed by estimating the rate of substrate diffusion per unit interfacial area (kSLC0) against the reaction rate per unit area (φr0/a). The rate of substrate diffusion per unit interfacial area was 0.0151 mol/(cm2 s). The reaction rate per unit area was 2.27 × 10−7 mol/(cm2 s). The values prove that the reaction is devoid of intraparticle diffusion
Figure 4. Effect of catalyst loading. (Reaction condition: 2-aminophenol = 1.0 mmol, vinyl acetate = 3.0 mmol, T = 50 °C, THF up to 10 mL, Novozym 435, speed of agitation = 250 rpm, time = 10 h.) 18530
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than those required for the reaction. Therefore, 4.67 mg/cm3 was considered as the optimized loading for the studied reaction. 2.5. Estimation of External Mass Transfer Resistance and Intra-particle Diffusion Limitation. The effect of speed of agitation on the initial rate of reaction was studied, and the concentration profiles were recorded. The relevant estimation of time constant, diffusivity, diffusion per unit area, and reaction rate per unit area was done as explained in detail in our previous work49,50 as well as using published reviews on the effect of supports on enzyme activity.2,4−7,16−18 The absence of both external and intraparticle diffusion resistances was confirmed using theoretical methods. Because it was a commercial enzyme, particle size variation was not possible. The rate of substrate diffusion per unit interfacial area is higher than the reaction rate per unit area. This proved that the reaction is devoid of intraparticle diffusion resistance. Thus, it was kinetically controlled. 2.6. Effect of Mole Ratio. The conversion of the reaction was evaluated at different concentrations of the acyl donor at a constant concentration of 2-aminophenol. The mole of vinyl acetate added to the reaction was varied over the range of 1.0− 10.0 mmol (Figure 5). The mole ratio with a value of 1:5 has the
Figure 6. Reaction condition: 2-aminophenol = 1.0 mmol, vinyl acetate = 5.0 mmol, T = 30−60 °C, THF up to 10 mL, Novozym 435 = 0.0075 g/mL, speed of agitation = 250 rpm, time = 10 h.
The activation energy for transesterification of 2-aminophenol was 4.5 kcal/mol (Figure S1 in the Supporting Information). 2.8. Study of Reusability. The reusability of the catalyst was assessed by separating the catalyst by filtration and flushing with THF to remove adsorbed impurities without changing the catalyst activity. The catalyst was then dried and weighed to use in further reactions. The protocol was repeated up to three batches. There was hardly any difference in the reaction conversion (∼2%). The data are represented in Figure 7. Hence, the catalyst is reusable, and the process can be commercialized efficiently. 2.9. Kinetic Study. A series of experiments were designed systematically to predict the reaction mechanism over a vast range of mole ratios. The mole of vinyl acetate was changed over
Figure 5. Effect of mole ratio. (Reaction condition: 2-aminophenol = 1.0 mmol, vinyl acetate = 1.0−10 mmol, T = 50 °C, THF up to 10 mL, Novozym 435 = 0.0075 g/mL, speed of agitation = 250 rpm, time = 10 h).
optimal conversion of 67.9%. When the moles of vinyl acetate were increased, it showed an inhibitory effect on lipase activity. Therefore, at 1:10 mole ratio, the conversion of the reaction dropped to 60.3%. 2.7. Effect of Different Temperatures. The experiments were designed by varying the temperature in the range of 30−60 °C. Conversion was 36.5% at 30 °C. At 50 and 60 °C, there was no change in the initial rate of reaction, which implies the initiation of intraparticle diffusion limitation. The initial rate of reaction at 40 °C was significantly lower than that at 60 °C. The conversion of the reaction at 60 °C was 74.6%, and it was selected as the optimal temperature (Figure 6). The plot of initial rates against the reciprocal of the temperature can be processed to estimate the activation energy. For enzymatic reactions, the activation energy is in the range of 3−10 kcal/mol.
Figure 7. Reusability study of the catalyst. 18531
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[A] and vinyl acetate [B]. Lipase showed inhibition with vinyl acetate [B]. The rate expression can be written as (eq 2)
the range of 0.5−10 mmol to analyze the initial rates of reaction. Similarly, a set of experiments was repeated for 2-aminophenol with other conditions remaining the same. The initial rate and conversion data were further processed to suggest a model for the reaction. The rate of reaction was increased with an increase in concentration of vinyl acetate (B) up to 5 mmol. A further increase in the concentration of vinyl acetate led to a slight inhibition by the vinyl acetate−lipase complex. Meanwhile, in the case of 2-aminophenol (A), the rate of reaction increases with increase in the concentration of 2-aminophenol. The Lineweaver−Burk plot gave an estimate of the plausible reaction mechanism, wherein the inverse of initial rates (r0) versus the inverse of 2-aminophenol concentration was plotted at a constant concentration of vinyl acetate (Figure 8). The
r0 =
K iK mB
rm[A][B] + K mB[A] + K mA[B] + [A][B]
(2)
where KmA is the Michaelis constant for 2-aminophenol (M), KmB is the Michaelis constant for vinyl acetate (M), Ki is the constant for inhibition due to the vinyl acetate−lipase dead end inhibitory complex (M), r0 and rm are the initial reaction rate and maximum rate, respectively (M/min). To verify the above proposed model, theoretical values of the constants were predicted using the Polymath 6.0 software (95% confidence level). The estimated kinetic parameters are tabulated in Table 1. Table 1. Estimated Kinetic Parameters for Chemoselective Acetylation of 2-Aminophenol with Vinyl Acetate kinetic parameters
values by Polymath 6.0
rm (M/min) KmA (M) KmB (M) Ki
0.01 0.035 0.021 0.12
An excellent fit of the parity plot of the predicted versus experimental rate of reaction implied significant correlation for the proposed model (parity plot Figure S2 in Supporting Information).
3. CONCLUSIONS Monoacetylation of 2-aminophenol using an appropriate acylating agent is useful in the pharmaceutical industry. In this work, enzymatic catalysis was used to prepare N-(2hydroxyphenyl)acetamide, which is a precursor for antimalarial drugs. A variety of vinyl esters were used as acyl donors in the presence of Novozym 435, which is a supported Cal B lipase, for this chemoselective reaction. The support is hydrophobic and there is an interfacial interaction, which leads to better activity. Vinyl acetate gave the best results. Immobilized enzyme activity in this kinetically controlled reaction is dependent on the adsorption of 2-aminophenol on the active center of Cal B, the specificity of the enzyme versus the active acyl donor (vinyl acetate) and N-(2-hydroxyphenyl)acetamide. A systematic study was done to optimize the reaction parameters. A ternary complex mechanism was predicted based on the observations of Lineweaver−Burk plots. It was observed that the reaction was associated with inhibition by vinyl acetate, and kinetic constants were estimated using the Polymath 6.0 software. Under the final optimized conditions, the conversion for the reaction was found to be 74.6% in 10 h at 50 °C.
Figure 8. Lineweaver−Burk plot: 1/[initial rate] vs 1/[A] at different concentrations of [B] (blue color circle solid: 1.0 mmol; orange color circle solid: 0.5 mmol; gray color circle solid: 0.33 mmol; yellow color circle solid: 0.2 mmol; blue color circle solid: 0.1 mmol of vinyl acetate concentration).
series of converging lines indicated a ternary complex mechanism, wherein the reaction showed inhibition with vinyl acetate. In this mechanism, both the products get released simultaneously from the active site of the lipase.43,44 The representation of the mechanism of reaction in the form of Cleland’s notation is given as below.
4. MATERIALS AND METHODS According to the literature reported on transesterification reactions by lipases, it is assumed that 2-aminophenol [A] and vinyl acetate [B] are bound to the lipase [E] without the release of any product and give rise to an intermediate lipase−2aminophenol substrate complex [EAB], which then breaks down in the product N-acetylated 2-aminophenol [P] and vinyl alcohol [Q] along with the release of lipase [E]. The released lipase can then proceed to react with available 2-aminophenol
4.1. ENZYME AND CHEMICALS 2-Aminophenol (Sigma-Aldrich, India), n-hexane, toluene, tetrahydrofuran (THF), 1, 4-dioxane, vinyl butyrate, vinyl acetate, and phenyl acetate (Thomas Baker (Chemicals) Pvt Ltd, Mumbai, India) were used during the research without any further purification. Novozym South Asia Pvt. Ltd. provided commercial Novozym 435 as a gift sample. 18532
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(5) Mateo, C.; Palomo, J. M.; Fernandez-Lorente, G.; Guisan, J. M.; Fernandez-Lafuente, R. Improvement of enzyme activity, stability and selectivity via immobilization techniques. Enzyme Microb. Technol. 2007, 40, 1451−1463. (6) Fernandez-Lafuente, R.; Armisen, P.; Sabuquillo, P.; FernandezLorente, G.; Guisan, J. M. Immobilization of lipases by selective adsorption on hydrophobic supports. Chem. Phys. Lipids 1998, 93, 185−97. (7) Tischer, W.; Wedekind, F. Immobilized Enzymes: Methods and Applications. In Biocatalysis - From Discovery to Application; Topics in Current Chemistry; Fessner, W. D.;et al., Ed.; Springer: Berlin, Heidelberg, 1999; Vol. 200. (8) Akil, E.; Carvalho, T.; Bárea, B.; Finotelli, P.; Lecomte, J.; Torres, A. G.; Amaral, P.; Villeneuve, P. Accessing regio-and typo-selectivity of Yarrowia lipolytica lipase in its free form and immobilized onto magnetic nanoparticles. Biochem. Eng. J. 2016, 101−111. (9) Rodrigues, D. S.; Mendes, A. A.; Filice, M.; Fernandez-Lafuente, R.; Guisan, J. M.; Palomo, J. M. Different derivatives of a lipase display different regioselectivity in the monohydrolysis of per-O-acetylated 1O-substituted-β-galactopyranosides. J. Mol. Catal. B: Enzym. 2009, 58, 36−40. (10) Zhang, D. H.; Bai, S.; Sun, Y. Lipase-catalyzed regioselective synthesis of monoester of pyridoxine (vitamin B6) in acetonitrile. Food Chem. 2007, 102, 1012−1019. (11) Rogalska, E.; Nury, S.; Douchet, I.; Verger, R. Lipase stereoselectivity and regioselectivity toward three isomers of dicaprin: A kinetic study by the monomolecular film technique. Chirality 1995, 7, 505−515. (12) Happe, M.; Kouadio, M.; Treanor, C.; Sawall, J. P.; Fornage, A.; Sugnaux, M.; Fischer, F. Size selectivity in lipase catalysed tetrol acylation. J. Mol. Catal. B: Enzym. 2014, 109, 40−46. (13) Leonte, D.; Bencze, L. C.; Paizs, C.; Irimie, F. D.; Zaharia, V. Heterocycles 38. Biocatalytic synthesis of new heterocyclic mannich bases and derivatives. Molecules 2015, 20, 12300−12313. (14) Zhang, L.; Li, F.; Wang, C.; Zheng, L.; Wang, Z.; Zhao, R.; Wang, L. Lipase-Mediated Amidation of Anilines with 1,3-Diketones via C−C Bond Cleavage. Catalysts 2017, 7, 115 DOI: 10.3390/catal7040115. (15) Yadav, G. D.; Sajgure, A. D.; Dhoot, S. B. Insight into Microwave Irradiation and Enzyme Catalysis in Enantioselective Resolution of RS (±) Methyl Mandelate. J. Chem. Technol. Biotechnol. 2008, 83, 1145− 1153. (16) dos Santos, J. C. S.; Barbosa, O.; Ortiz, C.; Berenguer-Murcia, A.; Rodrigues, R. C.; Fernandez-Lafuente, R. Importance of the Support Properties for Immobilization or Purification of Enzymes. ChemCatChem 2015, 7, 2413−2432. (17) Klaus, M. Immobilized Enzymes and Cells, Part C; Elsevier, 1987; Vol. 136, pp 3−584. (18) Sheldon, R. A.; van Pelt, S. Enzyme immobilisation in biocatalysis: why, what and how. Chem. Soc. Rev. 2013, 42, 6223−6235. (19) Kasche, V.; Haufler, U.; Riechmann, L. [26] Equilibrium and kinetically controlled synthesis with enzymes: Semisynthesis of penicillins and peptides. In Immobilized Enzymes and Cells, Part C: Methods in Enzymology; Mosbach, K., Ed.; Academic Press: Orlando, 1987; Vol. 136, pp 280−292. (20) van Roon, J. L.; Arntz, M. M. H. D.; Kallenberg, A. I.; Paasman, M. A.; Tramper, J.; Schroën, C. G. P. H.; Beeftink, H. H. A multicomponent reaction−diffusion model of a heterogeneously distributed immobilized enzyme. Appl. Microbiol. Biotechnol. 2006, 72, 263−278. (21) Yadav, G. D.; Devendran, S. Microwave Assisted Enzyme Catalysis: Practice and Perspective. In White Biotechnology for Sustainable Catalysis; Coelho, M. A. Z., Ribeiro, B. D., Eds.; RSC: London, 2015; Chapter 4, pp 52−103. (22) https://www.novozymes.com/en/advance-your-business/ pharma/pharma-biocatalysts. (23) Yadav, G. D.; Lathi, P. S. Intensification of enzymatic synthesis of propylene glycol monolaurate from 1, 2-propanediol and lauric acid under microwave irradiation: kinetics of forward and reverse reactions. Enzyme Microb. Technol. 2006, 38, 814−820.
4.2. Reaction Protocol. A glass reactor with four inbuilt baffles (30 cm3) was used for the reaction with an initial reaction mixture of 1.0 mmol 2-aminophenol, 5 mmol vinyl acetate, and 60 mg Novozym 435 in tetrahydrofuran as the solvent (made up to 15 cm3). The temperature and speed of agitation were maintained at 50 °C, using a thermostatic bath, and 200 rpm, respectively. 4.3. Analytical Method. An Agilent 1220 HPLC with a UV detector and a C18 column (250 mm × 4.6 mm i.d. dimension) was employed for gradient analysis. The composition of the elution phase used was acidic water (1% trifluoroacetic acid)/ acetonitrile (90:10) at a flow rate of 1.0 mL/min with column temperature set at 35 °C. The gradient structure is given in the Supporting Information. A multiple point method was applied to plot concentrations against time for the estimation of initial rates. The progress of the reaction was monitored with intermittent sampling. The product was confirmed by gas chromatography−mass spectrometry (Trace 1330 GC assembled with an ISQ LT single quadrupole mass spectrometer).
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01428.
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Kinetic parameters and parity plots (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel.: +91-22-3361-1001. Fax: +91-22-3361-1002/1020. ORCID
Ganapati D. Yadav: 0000-0002-8603-3959 Funding
This study was funded by the University Grants Commission (UGC). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS D.B.M. acknowledges the University Grants Commission (UGC) for awarding a Senior Research Fellowship under its Bioprocess Technology special meritorious fellowship program. G.D.Y. acknowledges support from the Endowments for R. T. Mody Distinguished Professor, the Tata Chemicals Darbari Seth Distinguished Professor of Leadership and Innovation, and also J. C. Bose National Fellowship of the Department of Science and Technology, Government of India.
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REFERENCES
(1) Sheldon, R. A.; Woodley, J. M. Role of Biocatalysis in Sustainable Chemistry. Chem. Rev. 2018, 118, 801−838. (2) Buchholz, K.; Kasche, V.; Bornscheuer, U. T. Immobilization of enzymes (Including Applications). In Biocatalysts and Enzyme Technology, 2nd ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2012; pp 243−253. (3) Heterogeneous Enzyme Kinetics. In Enzyme Biocatalysis: Principles and Applications; Illanes, A., Ed.; Springer, 2008; pp 155−203. (4) Rodrigues, R. C.; Ortiz, C.; Berenguer-Murcia, A.; Torres, R.; Fernandez-Lafuente, R. Modifying enzyme activity and selectivity by immobilization. Chem. Soc. Rev. 2013, 42, 6290−6307. 18533
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DOI: 10.1021/acsomega.8b01428 ACS Omega 2018, 3, 18528−18534
